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Drug Absorption (drug + absorption)
Selected AbstractsPopulation pharmacokinetics of pyrazinamide in elephantsJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 5 2005M. ZHU This study was undertaken to characterize the population pharmacokinetics (PK), therapeutic dose, and preferred route of administration for pyrazinamide (PZA) in elephants. Twenty-three African (Loxodonta africana) and Asian (Elephas maximus) elephants infected with or in contact with others culture positive for Mycobacterium tuberculosis were dosed under treatment conditions. PZA was dosed daily at 20,30 mg/kg via oral (fasting or nonfasting state) or rectal (enema or suppository) administration. Blood samples were collected 0,24 h postdose. Population PK was estimated using nonlinear mixed effect modeling. Drug absorption was rapid with Tmax at or before 2 h regardless of the method of drug administration. Cmax at a mean dose of 25.6 (±4.6) mg/kg was 19.6 (±9.5 ,g/mL) for PZA given orally under fasting conditions. Under nonfasting conditions at a mean dose of 26.1 ± 4.2 mg/kg, Cmax was 25% (4.87 ± 4.89 ,g/mL) and area under concentration curve (AUC) was 30% of the values observed under fasting conditions. Mean rectal dose of 32.6 ± 15.2 mg/kg yielded Cmax of 12.3 ± 6.3 ,g/mL, but comparable AUC to PZA administered orally while fasting. Both oral and rectal administration of PZA appeared to be acceptable and oral dosing is preferred because of the higher Cmax and lower inter-subject variability. A starting dose of 30 mg/kg is recommended with drug monitoring between 1 and 2 h postdose. Higher doses may be required if the achieved Cmax values are below the recommended 20,50 ,g/mL range. [source] Pharmacokinetics of E-6087, a new anti-inflammatory agent, in rats and dogsBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 6 2001Raquel F. Reinoso Abstract The pharmacokinetics of E-6087, a newly developed cyclooxygenase-2 inhibitor, was studied in rats and dogs after single oral and intravenous doses. In both animal species, E-6087 was characterized by a long elimination half-life (20,35 h), a low plasma clearance (0.10,0.22 l h,1 kg,1) and a relatively large volume of distribution (2,6 l kg,1). Oral bioavailability was lower in dogs than in rats whereas a faster elimination was found in rats. Multiple peaks were present regardless of administration route and animal species, suggesting the existence of enterohepatic circulation. Gender effect on the pharmacokinetics of E-6087 was only found in rats, with greater exposure and longer elimination in females than in males. Food intake reduced the bioavailability (,22%) with no apparent changes in the absorption rate. After oral dosing of 1, 5 and 25 mg kg,1 to rats, linearity was lost at the highest dose due to the low aqueous solubility of E-6087. Drug absorption was improved by micronization. E-6087 and E-6132, (a pharmacologically active metabolite), showed different pharmacokinetics. The higher percentage of E-6087 at early times suggests that E-6087 is the main compound responsible for in vivo activity, although E-6132 would contribute to the activity at later times. Copyright © 2001 John Wiley & Sons, Ltd. [source] Organic anion-transporting polypeptide (OATP) transporter family and drug dispositionEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 2003R. B. Kim Abstract Drug transporters are increasingly recognized as a key determinant of drug disposition. Recent studies have revealed that targeted expression of drug uptake and efflux transporters to specific cell membrane domains allows for the efficient directional movement of many drugs in clinical use. While the role of certain efflux transporters such as MDR1 (P-glycoprotein) in drug disposition has been extensively studied, emerging evidence suggests that uptake transporters may also be important to the intestinal absorption and renal or hepatic elimination of drugs. Members of the organic anion-transporting polypeptide (OATP) family of drug uptake transporters have been found capable of transporting a large array of structurally divergent drugs. Moreover, expression of OATP isoforms in the gastrointestinal tract, liver and kidney, as well as at the level of the blood,brain barrier, has important implications for our understanding of the factors governing drug absorption, elimination and tissue penetration. [source] Altered pharmacology in the intensive care unit patientFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 5 2008Giovanni Zagli Abstract Critically ill patients, not infrequently present alterations of physiological parameters that determine the success/failure of therapeutic interventions as well as the final outcome. Sepsis and polytrauma are two of the most common and complex syndromes occurring in Intensive Care Unit (ICU) and affect drug absorption, disposition, metabolism and elimination. Pharmacological management of ICU patients requires consideration of the unique pharmacokinetics associated with these clinical conditions and the likely occurrence of drug interaction. Rational adjustment in drug choice and dosing contributes to the appropriateness of treatment of those patients. [source] Drug metabolism and disposition in childrenFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 3 2003M. Strolin Benedetti Abstract Key factors undergoing maturational changes accounting for differences in drug metabolism and disposition in the pediatric population compared with adults are reviewed. Gastric and duodenal pH, gastric emptying time, intestinal transit time, bacterial colonization and probably P-glycoprotein are important factors for drug absorption, whereas key factors explaining differences in drug distribution between the pediatric population and adults are membrane permeability, plasma protein concentration and plasma protein characteristics, endogenous substances in plasma, total body and extracellular water, fat content, regional blood flow and probably P-glycoprotein, mainly that present in the gut, liver and brain. As far as drug metabolism is concerned, important differences have been found in the pediatric population compared with adults both for phase I enzymes [oxidative (e.g. cytochrome CYP3A7 vs. CYP3A4 and CYP1A2), reductive and hydrolytic enzymes] and phase II enzymes (e.g. N -methyltransferases and glucuronosyltransferases). Finally, key factors undergoing maturational changes accounting for differences in renal excretion in the pediatric population compared with adults are glomerular filtration and tubular secretion. It would be important to generate information on the developmental aspects of renal P-glycoprotein and of other renal transporters as done and still being done with the different isozymes involved in drug metabolism. [source] Influence of administration vehicles and drug formulations on the pharmacokinetic profile of lamotrigine in ratsFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 5 2002M. M. Castel-Branco Abstract Given that administration vehicles and drug formulations can affect drug bioavailability, their influence on the pharmacokinetic profile of lamotrigine (LTG), a new-generation anti-epileptic drug, was studied in rats. Three different formulations administered intraperitoneally at a dose of 10 mg/kg were used: (1) LTG suspended in a 0.25% methylcelulose solution, (2) LTG dissolved in a 50% propylene glycol solution, and (3) LTG isethionate dissolved in distilled water. Plasma and brain homogenate levels were determined in order to evaluate vehicle-dependent drug absorption. The results demonstrated rapid absorption of LTG when it was administered as an aqueous solution, in contrast to a slower and more erratic absorption after the injection of either the lipophilic solution or the suspension. A plasma peak was achieved 15 min post-dose with the aqueous solution, with a brain peak being achieved 15 min later, while with the other formulations both plasma and brain homogenate peaks were reached 2 h after LTG administration. This study suggests that LTG isethionate dissolved in distilled water is the most suitable formulation for successful LTG pharmacokinetic studies in rats. [source] Syntheses of [14C]BAY 59-7939 and its radiolabeled metabolite M-4JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS, Issue 11 2006U. Pleiss Abstract BAY 59-7939 is a novel, oral, direct Factor Xa inhibitor in clinical development for the prevention and treatment of thromboembolic diseases. Radiolabeled BAY 59-7939 was required for drug absorption, distribution, metabolism and excretion (ADME studies). The BAY 59-7939 was labeled with carbon-14 in the carboxamide group in one step in an overall radiochemical yield of 85% starting from 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}mor-pholin-3-one and 5-chlorothiophene-2-[14C]carboxylic acid. The radiolabeled metabolite M-4 was prepared in 77% yield starting from [1- 14C]glycine and 5-chlorothiophene-5-carboxylic acid. Copyright © 2006 John Wiley & Sons, Ltd. [source] Syntheses of [2H3, 15N], [14C]NexavarŌ and its labeled metabolitesJOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS, Issue 7 2006U. Pleiss Abstract NexavarŌ, Sorafenib tosylate (BAY 43-9006 tosylate) is a potent small molecule Raf kinase inhibitor for the treatment of hyperproliferative disorders such as cancer. Both radiolabeled and stable isotope labeled compounds were required for drug absorption, distribution, metabolism and excretion (ADME) and quantitative mass spectrometry bio-analytical studies. NexavarŌ labeled with carbon-14 in the carboxamide group was prepared in two steps in an overall radiochemical yield of 42% starting from 4-chloro- N -methyl-2-pyridine-[14C]carboxamide. The [2H3,15N] version of NexavarŌ was prepared in 75% yield based on 4-chloro- N -[2H3]methyl-2-pyridine-[15N]carboxamide. The pyridine N -oxide metabolite labeled with carbon-14 as well as with deuterium and nitrogen-15 and was synthesized by oxidation in yields of 59% and 87%, respectively. Starting from [2H2, 13C]formaldehyde the N -hydroxymethyl metabolite was labeled with carbon-13 and deuterium in one step in a 45% overall yield. Copyright © 2006 John Wiley & Sons, Ltd. [source] The species differences of intestinal drug absorption and first-pass metabolism between cynomolgus monkeys and humansJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 11 2009Masayuki Takahashi Abstract In order to elucidate the causes of the species differences in the oral bioavailability (BA) between cynomolgus monkeys and humans, the contributions of first-pass metabolism and intestinal absorption were investigated. Typical substrates of cytochrome P450 enzymes, UDP-glucuronosyltransferase enzymes and efflux transporters were selected, and the BA, the hepatic availability (Fh) and the fraction dose absorbed from gastro-intestinal tract (Fa*Fg) were calculated from pharmacokinetic analysis after oral and intravenous administration in cynomolgus monkeys. In addition, in vitro metabolism was investigated using liver and intestinal microsomes to evaluate the relationship between in vivo and in vitro results. The BA of cynomolgus monkeys was low compared with that in humans with most of the drugs tested, and not only Fh but also Fa*Fg contributed significantly to the low BA in cynomolgus monkeys. When Fh was evaluated in in vitro experiments, it correlated well with the in vivo Fh. However, although the metabolic activities of CYP3A4 substrates were high in cynomolgus monkey intestinal microsomes, those of the other substrates were low or not detected. These findings suggested that the species differences and low BA in cynomolgus monkeys could be mostly attributed not only to hepatic first-pass metabolism but also to the intestinal absorption process. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:4343,4353, 2009 [source] Investigation of human pharmacoscintigraphic behavior of two tablets and a capsule formulation of a high dose, poorly water soluble/highly permeable drug (efavirenz)JOURNAL OF PHARMACEUTICAL SCIENCES, Issue 11 2007J. ZH. Abstract Human pharmacoscintigraphic behavior of two tablets and a capsule formulation of a high dose, poorly water soluble, highly permeable, micronized drug (efavirenz) was investigated. The tablets and capsule, prepared with samarium oxide and neutron activated to produce radioactive samarium-153, were evaluated for their in vivo disintegration and gastrointestinal (GI) transit in healthy subjects under fasted condition. Scintigraphic images were acquired to coincide with blood sampling times to assess the plasma concentration-time profile in relation to in vivo disintegration and GI transit. The mean gastric emptying times were approximately the same for all three formulations. Although in vivo dosage form disintegration was faster for Tablet A as compared to Tablet B and was similar between Tablet A and the capsule, Tablet A showed a slower rate and extent of drug absorption than Tablet B and the capsule. The results of this study eliminated the initial hypothesis that the difference in in vivo performance between the two tablet formulations is due to a different rate of in vivo disintegration and suggest that for this drug the in vivo dissolution rate of the drug from its disintegrated dosage form was a more important factor affecting the rate and extent of drug absorption. © 2007 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 96: 2970,2977, 2007 [source] Air-liquid interface (ALI) culture of human bronchial epithelial cell monolayers as an in vitro model for airway drug transport studiesJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 2 2007Hongxia Lin Abstract Serially passaged normal human bronchial epithelial (NHBE) cell monolayers were established on Transwell® inserts via an air-liquid interface (ALI) culture method. NHBE cells were seeded on polyester Transwell® inserts, followed by an ALI culture from day 3, which resulted in peak TEER value of 766,±,154 ,,×,cm2 on the 8th day. Morphological characteristics were observed by light microscopy and SEM, while the formation of tight junctions was visualized by actin staining, and confirmed successful formation of a tight monolayer. The transepithelial permeability (Papp) of model drugs significantly increased with the increase of lipophilicity and showed a good linear relationship, which indicated that lipophilicity is an important factor in determining the Papp value. The expression of P-gp transporter in NHBE cell monolayers was confirmed by the significantly higher basolateral to apical permeability of rhodamine123 than that of reverse direction and RT-PCR of MDR1 mRNA. However, the symmetric transport of fexofenadine,·,HCl in this NHBE cell monolayers study seems to be due to the low expression of P-gp transporter and/or to its saturation with high concentration of fexofenadine,·,HCl. Thus, the development of tight junction and the expression of P-gp in the NHBE cell monolayers in this study imply that they could be a suitable in vitro model for evaluation of systemic drug absorption via airway delivery, and that they reflect in vivo condition better than P-gp over-expressed cell line models. ©2006 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 96:341,350, 2007 [source] Influence of the intermediate digestion phases of common formulation lipids on the absorption of a poorly water-soluble drugJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 3 2005Greg A. Kossena Abstract The influence of different model intestinal phases (modelled on those likely to be produced in vivo after the digestion of commonly used formulation lipids) on the absorption profile of cinnarizine has been studied. Combinations of C8, C12, or C18:1 fatty acid and monoglyceride and simulated endogenous intestinal fluid were formulated to provide examples of liquid (L1), lamellar (L,), and cubic (C) liquid crystalline phases. Phases containing cinnarizine were dosed intraduodenally and absorption was assessed in an anesthetized rat model. Bile duct ligation was performed to inhibit the effects of digestion/dilution on the phase structure. Absorption from the L, phases (C8 and C12 lipids) was statistically higher (p,<,0.05) than a cinnarizine suspension: however, a statistically significant difference was not observed from the L1 and C phases. The rigid C18:1 C phase showed evidence of providing for sustained drug absorption. Experiments in bile intact rats with the C8 L, and C18:1 C phase highlighted that the absorption-modifying properties of these phases were influenced by dilution in the endogenous bile milieu, with absorption from L, phase reducing (possibly through precipitation of solubilized drug) and increasing in the case of the C18:1 C phase, possibly through the coexistence of L1 and C upon dilution permitting more efficient transfer of solubilized drug. © 2004 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 94:481,492, 2005 [source] Biological, pharmaceutical, and analytical considerations with respect to the transport media used in the absorption screening system, Caco-2JOURNAL OF PHARMACEUTICAL SCIENCES, Issue 8 2003Franēoise M. Ingels Abstract During the evaluation and selection of drug candidates, the Caco-2 cell culture system is commonly used for the determination of intestinal transport characteristics and to anticipate permeability limited drug absorption. Although classic HBSS-like buffered salt solutions are commonly used to perform Caco-2 transport experiments, different shortcomings (e.g., adsorption and low solubility) have been associated with the use of plain aqueous buffers. As transport experiments performed with unoptimized conditions may compromize the value of the Caco-2 model as a permeation screening tool, many efforts have been made to optimize the experimental conditions of Caco-2 transport assays. In this minireview, the hurdles associated with the use of saline aqueous buffers in Caco-2 transport experiments are summarized and the different options, which have been proposed to overcome these issues, are reviewed and discussed. Biologically, pharmaceutically, as well as analytically relevant media affecting the outcome of the transport experiments are described. Unfortunately, up to now, no systematic studies comparing the different experimental conditions have been performed, jeopardizing the possibility to define a (single) optimal solution to overcome the different issues associated with the use of saline aqueous buffers. Based on the reported options it can be proposed to use DMSO (,1%) in standard screening procedures for the ranking of compounds based on their apical to basolateral transport. If compounds are not soluble in DMSO 1%, dimethylacetamide (3%) or N -1-methyl-pyrrolidone (2.5%) are good alternatives. However, these options do not imitate the in vivo situation. If one wants to take into account the physiological relevance of the media, the use of a biologically relevant apical medium (e.g., FASSIF) in combination with an analytically friendly, sink condition creating basolateral solvent (e.g., containing a micelle forming agent) can be suggested. © 2003 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 92:1545,1558, 2003 [source] Mechanisms of cytoprotective effect of amino acids on local toxicity caused by sodium laurate, a drug absorption enhancer, in intestinal epitheliumJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 3 2002Yoko Endo Abstract Several amino acids, including L -glutamine (L -Gln), were found to protect the intestinal epithelial cells from the local toxicity caused by a drug absorption enhancer, sodium laurate (C12), in our previous study. To develop more efficient and safer formulations for enhancing drug absorption, the mechanisms of cytoprotection by amino acids were studied using rats and Caco-2 cells. Four amino acids, including L -Gln, could generally maintain the absorption-promoting action of C12, although taurine tended to attenuate it. Three amino acids, except for L -Gln, significantly suppressed the decrease in the transepithelial electrical resistance caused by C12. Quercetin, an inhibitor for biosynthesis of heat shock protein 70 (HSP70), masked only the protective effect of L -Gln in both rat large intestine and Caco-2 cells. Western blot analysis indicated clearly that HSP70 is induced extensively only by the addition of L -Gln in both rat large-intestinal cells and Caco-2 cells. C12 was found to increase the intracellular concentration of Ca2+ ([Ca2+]i) remarkably, and amino acids, especially L -arginine, L -methionine, and taurine, significantly attenuated the increase in [Ca2+]i caused by C12. Furthermore, although C12 stimulated the release of histamine, an inflammatory mediator, from rat large-intestinal tissue, amino acids were also found to suppress the release of histamine enhanced by C12. The results in the present study showed that an induction of HSP70, a decrease in [Ca2+]i elevated by C12, and a suppression of histamine release stimulated by C12 should be involved in the mechanisms behind the cytoprotective action of amino acids against the local toxicity caused by C12. © 2002 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 91:730,743, 2002 [source] Amino acids protect epithelial cells from local toxicity by absorption enhancer, sodium laurateJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 10 2001Takashi Yata Abstract To develop the safe absorption-enhancing formulation attenuating the local toxicity caused by an absorption enhancer, sodium laurate (C12), the effects of amino acids on the local toxicity by C12 were examined in rats. The absorption of phenol red, an unabsorbable marker drug, was significantly enhanced by 10 mM C12 in an in situ colon loop study and the addition of L -glutamine (L -Gln), L -arginine, or L -methionine at 10 mM did not change the promoting effect of C12. However, C12 significantly increased the elution of phospholipids, total protein, and lactate dehydrogenase, which are markers for local toxicity, from colon, but these amino acids attenuated the local toxicity caused by C12 significantly. Transport study using an Ussing-type chamber showed that the permeability of colonic membrane to phenol red was significantly enhanced by C12 and that L -Gln did not decrease the permeability enhanced by C12. Transmucosal electrical resistance was extensively decreased by C12, indicating that C12 could enhance the drug absorption at least partly by expanding the paracellular route. L -Gln significantly, but not completely, recovered resistance lowered by C12. Electrical potential difference was markedly reduced by C12, suggesting that C12 lowered the viability of mucosal cells, but 10 mM L -Gln significantly recovered potential difference almost to the control level. These results suggested the possibility that absorption-enhancing formulation with low local toxicity, which is low enough to be used practically, could be developed by using an amino acid like L -Gln as an ingredient attenuating the local toxicity caused by C12. © 2001 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 90:1456,1465, 2001 [source] In-vitro permeation of drugs into porcine hair follicles: is it quantitatively equivalent to permeation into human hair follicles?JOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 2 2008Yakov Frum It is already well-established that the general permeability properties of porcine skin are close to those of human skin. However, very little is known with respect to drug absorption into hair follicles and the similarities if any between the two types of tissue. The aim of this study was to use the skin sandwich system to quantify follicular drug absorption into porcine hair follicles. To our knowledge, this is the first time that the skin sandwich has been extended to porcine tissue. For this purpose, seven different drugs , estradiol, corticosterone, hydrocortisone, aldosterone, cimetidine, deoxyadenosine and adenosine , exhibiting a wide range of log octanol-water partition coefficients (log Ko/w), but comparable molecular weights, were chosen as candidate solutes. The results showed a parabolic profile with maximal follicular contribution occurring at intermediate log Ko/w values. Linear regression analysis indicated that the follicular contributions in porcine skin correlated well with previously published follicular contributions in human skin (r2 = 0.87). The novelty of this research is that we show that porcine tissue is a good surrogate for modelling human skin permeability within the specific context of quantifying drug absorption into hair follicles. [source] Prediction of human pharmacokinetics,gut-wall metabolismJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 10 2007Urban Fagerholm Intestinal mucosal cells operate with different metabolic and transport activity, and not all of them are involved in drug absorption and metabolism. The fraction of these cells involved is dependent on the absorption characteristics of compounds and is difficult to predict (it is probably small). The cells also appear comparably impermeable. This shows a limited applicability of microsome intrinsic clearance (CLint)-data for prediction of gut-wall metabolism, and the difficulty to predict the gut-wall CL (CLGW) and extraction ratio (EGW). The objectives of this review were to evaluate determinants and methods for prediction of first-pass and systemic EGW and CLGW in man, and if required and possible, develop new simple prediction methodology. Animal gut-wall metabolism data do not appear reliable for scaling to man. In general, the systemic CLGW is low compared with the hepatic CL. For a moderately extracted CYP3A4-substrate with high permeability, midazolam, the gut-wall/hepatic CL-ratio is only 1/35. This suggests (as a general rule) that systemic CLGW can be neglected when predicting the total CL. First-pass EGW could be of importance, especially for substrates of CYP3A4 and conjugating enzymes. For several reasons, including those presented above and that blood flow based models are not applicable in the absorptive direction, it seems poorly predicted with available methodology. Prediction errors are large (several-fold on average; maximum-15-fold). A new simple first-pass EGW -prediction method that compensates for regional and local differences in absorption and metabolic activity has been developed. It has been based on human cell in-vitro CLint and fractional absorption from the small intestine for reference (including verapamil) and test substances, and in-vivo first-pass EGW -data for reference substances. First-pass EGW -values for CYP3A4-substrates with various degrees of gastrointestinal uptake and CLint and a CYP2D6-substrate were well-predicted (negligible errors). More high quality in-vitro CLint - and in-vivo EGW -data are required for further validation of the method. [source] Intestinal drug absorption and bioavailability: beyond involvement of single transport functionJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 4 2003Hans Lennernäs [source] The biopharmaceutical aspects of nasal mucoadhesive drug deliveryJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 1 2001Michael Ikechukwu Ugwoke Nasal drug administration has frequently been proposed as the most feasible alternative to parenteral injections. This is due to the high permeability of the nasal epithelium, allowing a higher molecular mass cut-off at approximately 1000 Da, and the rapid drug absorption rate with plasma drug profiles sometimes almost identical to those from intravenous injections. Despite the potential of nasal drug delivery, it has a number of limitations. In this review, the anatomy and physiology of the nasal cavity, as well as ciliary beating and mucociliary clearance as they relate to nasal drug absorption, are introduced. The rationale for nasal drug delivery and its limitations, some factors that influence nasal drug absorption, and the experimental models used in nasal drug delivery research are also reviewed. Nasal mucoadhesion as a promising method of nasal absorption enhancement is discussed, and factors that influence mucoadhesion, as well as safety of nasal mucoadhesive drug delivery systems are reviewed in detail. Nasal drug administration is presently mostly used for local therapies within the nasal cavity. Anti-allergic drugs and nasal decongestants are the most common examples. However, nasal drug administration for systemic effects has been practised since ancient times. Nasally-administered psychotropic drugs by native Americans, the use of tobacco snuffs, and nasal administration of illicit drugs such as cocaine are all well known (Illum & Davis 1992). Nowadays, the nasal cavity is being actively explored for systemic administration of other therapeutic agents, particularly peptides and proteins (Illum 1992; Edman & Bjork 1992), as well as for immunization purposes (Lemoine et al 1998). To better understand the basis for nasal drug absorption and factors that can influence it, a brief review of the anatomy and physiology of the nose is appropriate. [source] Systematic review: impaired drug absorption related to the co-administration of antisecretory therapyALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 12 2009E. LAHNER Summary Background, Due to suppression of gastric acidity during antisecretory therapy, an impaired absorption of co-administered drugs may occur. Aim, To review evidence of impaired drug absorption related to the use of co-administered PPIs or H2RAs. Methods, Systematic search of MEDLINE/EMBASE/SCOPUS databases (1980,September 2008) for English articles with keywords: drug malabsorption and absorption, stomach, anti-secretory/acid inhibitory drugs, histamine H2 antagonists, PPIs, gastric acid, pH, hypochlorhydria, gastric hypoacidity. From 2126 retrieved articles, 16 randomized crossover studies were identified investigating impaired absorption of nine different drugs in association with co-administration of PPIs or H2RAs. Information on investigated drug, study type, features of investigated subjects, study design, type of intervention, and study results were extracted. Results, The identified studies investigated the absorption kinetics of nine drugs. Acid suppression reduced absorption of ketoconazole, itraconazole, atazanavir, cefpodoxime, enoxacin and dipyridamole (median Cmax reduction by 66.5%). An increased absorption of nifedipine and digoxin (median AUC increase by 10%) and a 2-fold-increase in alendronate bioavailability were observed. Conclusions, Gastric pH appears relevant for absorption of some cardiovascular or infectious disease agents. Antisecretory treatment may significantly modify the absorption of co-administered drugs. [source] Systematic review: Heliocobacter pylori infection and impaired drug absorptionALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 4 2009E. LAHNER Summary Background, Impaired acid secretion may affect drug absorption and may be consequent to corporal Heliocobacter pylori- gastritis, which may affect the absorption of orally administered drugs. Aim, To focus on the evidence of impaired drug absorption associated with H. pylori infection. Methods, Data sources were the systematic search of MEDLINE/EMBASE/SCOPUS databases (1980,April 2008) for English articles using the keywords: drug malabsorption/absorption, stomach, Helicobacter pylori, gastritis, gastric acid, gastric pH, hypochlorhydria, gastric hypoacidity. Study selection was made from 2099 retrieved articles, five studies were identified. Data were extracted from selected papers, investigated drugs, study type, main features of subjects, study design, intervention type and results were extracted. Results, In all, five studies investigated impaired absorption of l -dopa, thyroxine and delavirdine in H. pylori infection. Eradication treatment led to 21,54% increase in l -dopa in Parkinon's disease. Thyroxine requirement was higher in hypochlorhydric goitre with H. pylori- gastritis and thyrotropin levels decreased by 94% after treatment. In H. pylori- and HIV-positive hypochlorhydric subjects, delavirdine absorption increased by 57% with orange juice administration and by 150% after eradication. Conclusions, A plausible mechanism of impaired drug absorption is decreased acid secretion in H. pylori -gastritis patients. Helicobacter pylori infection and hypochlorhydria should be considered in prescribing drugs the absorption of which is potentially affected by intragastric pH. [source] Population pharmacokinetics of isoniazid in the treatment of Mycobacterium tuberculosis among Asian and African elephants (Elephas maximus and Loxodonta africana)JOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 1 2005J. N. MASLOW We recently described the clinical presentation and treatment of 18 elephants from six herds infected with TB. Treatment protocols and methods varied between herds to include both oral and rectal dosing using multiple drug doses and formulations. In this paper we present information regarding the pharmacokinetics (PK) of isoniazid (INH) in elephants and provide suggestions regarding initial treatment regimens. Forty-one elephants received INH daily by either oral or rectal administration with different formulations. Population PK analysis was performed using Non-linear Mixed Effect Modeling (NONMEM). Results of oral administration indicated that compared with premixed INH solution, the drug exposure was highest with a suspension prepared freshly with INH powder. When INH was concomitantly given as an admixture over food, Tmax was delayed and variability in drug absorption was significantly increased. Compared with oral administration, similar drug exposures were found when INH was dosed rectally. The data generated suggest that a starting dose of 7.5 mg/kg of INH is appropriate for initial TB treatment in elephants when premixed solution is administered directly into the oropharynx or rectal vault and 4 mg/kg are when INH is administered following immediate suspension from powdered form. [source] Medicine-taking behavior: Implications of suboptimal compliance in Parkinson's diseaseMOVEMENT DISORDERS, Issue 11 2005Katherine A. Grosset MBChB Abstract Management of Parkinson's disease (PD) depends primarily on oral medication. There are several drug classes and multiple doses and formulations, which make optimizing therapy complex. Variable drug absorption and the short half-life of most antiparkinson treatments, especially levodopa, are a main focus in understanding complications and have encouraged alternative delivery systems to limit fluctuation and dyskinesia at later stages. Comparatively little attention is paid to the way patients take their oral medication. Variable medicine-taking behavior can affect the clinician's understanding of the diagnosis and rate of progression, and further prescription of PD medication. Medicine overuse in later stage PD is well documented and causes psychiatric disturbance and increases motor complications, but evidence of undertreatment and erratic intake is emerging, which is likely to affect motor control and quality of life adversely. Methods of quantifying compliance are compared for accuracy and limitations. Understanding medicine-taking behavior is a first step in optimizing therapy and requires consideration of a patient's personal beliefs about their medicines. Although the benefits of regularizing oral medicine-taking in a practical, achievable way in PD remain untested, such an approach might prolong and smooth the benefits of oral medication and is worthy of further research. © 2005 Movement Disorder Society [source] The assessment of human regional drug absorption of free acid and sodium salt forms of Acipimox, in healthy volunteers, to direct modified release formulation strategyBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 9 2009Rajeev Menon Abstract Acipimox is an analog of nicotinic acid and is indicated for the treatment of dyslipidemia. It is also believed to improve glucose control by enhancing insulin sensitivity. The purpose of this study was to direct modified release (MR) formulation strategy by comparing the bioavailability of two forms of acipimox (free acid and sodium salt) from the distal small bowel (DSB) and colon with an immediate release formulation. Two parallel groups of healthy volunteers completed an open label, non-randomized, three-way crossover study. The rate and extent of acipimox absorption was highest following administration of the immediate release capsules, and was not influenced by the form of the drug administered. Following administration to the DSB, the relative bioavailability was approximately 52% and 30% for the salt form and free acid form, respectively. Following administration to the colon, the extent of absorption was further reduced. The data indicate that bioavailability from the DSB was limited by the solubility of the drug coupled with an absorption window, whilst absorption from the colon was limited by permeability. The study provided detailed information to support and guide the formulation strategy for a MR form of acipimox, which may improve the treatment of adult patients with type II diabetes and dyslipidemia. Copyright © 2009 John Wiley & Sons, Ltd. [source] Apparent active transport of MDMA is not mediated by P-glycoprotein: a comparison with MDCK and Caco-2 monolayersBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 5 2006Kirk M. Bertelsen Abstract Amphetamines and their methylenedioxy derivatives generically display similar behavioral, physiologic and toxic effects. Inconsistent pharmacokinetic and toxicity data for methylenedioxymethamphetamine (MDMA) may suggest that active drug transporters are interacting with these compounds, and thus altering drug absorption and tissue distribution. In vitro models of CNS accumulation and intestinal drug transport were used to assess efflux transport of MDMA. Madin-Darby kidney cell epithelial (MDCK) monolayers displayed a 4-fold increase in accumulation in the basolateral to apical orientation relative to the apical to basolateral orientation, although no differential accumulation was noted between MDCK-WT and MDCK-MDR1 monolayers. Caco-2 monolayers demonstrated an approximate 2-fold increase in accumulation of MDMA. Exposure of various inhibitors of active drug transporters demonstrated mixed results; ritonavir, progesterone and indomethacin produced an approximately 50% reduction of MDMA transport, while verapamil, MK-571 and probenecid had no effect. Based on these data, it is concluded that MDMA efflux is mediated via the activity of a transporter distinct from P-glycoprotein. The possible inhibitory effects of amphetamines on rhodamine-123 transport were also assessed. MDMA, methylenedioxyamphetamine, amphetamine and methamphetamine, at physiologically relevant concentrations, did not significantly alter the transport of rhodamine-123 in Caco-2 monolayers or the LS180 cell line, suggesting that these compounds do not alter the function of P-glycoprotein. Copyright © 2006 John Wiley & Sons, Ltd. [source] Does stereoselective lymphatic absorption contribute to the enantioselective pharmacokinetics of halofantrine In Vivo?BIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 4 2003David M. Shackleford Abstract Halofantrine (Hf) is a chiral, lipophilic phenanthrene methanol antimalarial which exhibits both enantioselective plasma pharmacokinetics and extensive lymphatic absorption when administered postprandially. In order to determine whether enantioselective lymphatic absorption contributes to the previously reported enantioselective pharmacokinetics of Hf, lymph samples collected from thoracic duct-cannulated dogs dosed with racemic Hf (100 mg, administered postprandially) were assayed with a chiral HPLC method capable of quantifying the relative amounts of (+)- and (,)-Hf. During the period when the majority (>95%) of Hf transport into lymph occurred (0,5 h post dose), essentially equal amounts of the two enantiomers were present in the intestinal lymph. At later times (e.g. 5,12 h post dose), there was a steady increase in the fraction of (+)-Hf present in lymph. The trends evident at later time points most likely reflect an increase in the proportion of (+)-Hf present in systemic blood, (resulting from enantioselective systemic metabolism) and a corresponding increase in (+)-Hf in the thoracic lymph by equilibration of drug across blood and lymphatic capillaries, as opposed to enantioselective lymphatic transport per se. This study was the first to examine the possibility of stereoselectivity in lymphatic transport, however, the data suggest that drug absorption (at least in the case of halofantrine) via the intestinal lymphatics is not enantioselective. Copyright © 2003 John Wiley & Sons, Ltd. [source] Pharmacokinetics of cysteamine bitartrate following gastrointestinal infusionBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 1 2007Meredith C. Fidler Aims Although cysteamine was first used in the treatment of cystinosis in 1976 and approved by the FDA as cysteamine bitartrate (CystagonŌ) in 1994, surprisingly little pharmacological data are available for this compound. Cysteamine and its related drugs are currently being evaluated for the treatment of Huntington's and Parkinson's disease. The aim of te study was to understand the pharmacokinetics of cysteamine bitartrate following gastrointestinal infusion. Method Cysteamine bitartrate was delivered through a naso-enteric catheter into the stomach (n = 8), small intestine (n = 8) and caecum (n = 4) of normal subjects. Plasma cysteamine concentrations were determined using LC-MS/MS. Results The rate and extent of drug absorption were assessed by comparing AUC(0, ,), Cmax and tmax, among the gastrointestinal infusion sites. Total cysteamine exposure, expressed as area under the curve (AUC(0, ,)) was greatest when the drug was infused into the small intestine (4331.3 ± 1907.6 min × µm) followed by stomach (3901.9 ± 1591.9 min × µm) and caecum (3141.4 ± 1627.6 min × µm). Cysteamine infusion into the small intestine resulted in the most rapid rise to maximal plasma concentrations (tmax = 21 ± 0.56 min); tmax was delayed to 50 ± 26 min and 64 ± 26 min after gastric and caecal infusion, respectively. The maximum cysteamine plasma concentration (Cmax) was reached after infusion of the drug into the small intestine (51 ± 21 µm), which was higher than plasma Cmax concentrations after gastric (39 ± 16 µm) and caecal infusion (23 ± 15 µm). Conclusions The pharmacokinetic data generated help extend our understanding of cysteamine. [source] Pharmacokinetics and systemic endocrine effects of the phyto-oestrogen 8-prenylnaringenin after single oral doses to postmenopausal womenBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 3 2006M. Rad Aims Pre-clinical data suggest that the racemic phyto-oestrogen 8-prenylnaringenin (8-PN) may have beneficial effects in postmenopausal women and may become an alternative to classical hormone replacement therapy (HRT) treatment regimes. The aim of this study was to investigate the pharmacokinetics, endocrine effects and tolerability of chemically synthesized 8-PN in postmenopausal women. Methods The study was performed using a randomized, double-blind, placebo-controlled, dose-escalation design with three groups of eight healthy postmenopausal women. In each group six subjects received 8-PN and two subjects placebo. 8-PN was given orally in doses of 50, 250 or 750 mg. Drug concentrations in serum, urine and faeces were measured up to 48 h and follicle-stimulating hormone/luteinizing hormone (LH) concentrations up to 24 h. Results All treatments were well tolerated and associated with a low incidence of (drug unrelated) adverse events. Serum concentrations of free 8-PN showed rapid drug absorption and secondary peaks suggestive of marked enterohepatic recirculation. Independent of the treatment group, approximately 30% of the dose was recovered in excreta as free compound or conjugates over the 48-h observation period. The first Cmax and AUC0,48 h showed dose linearity with ratios of 1 : 4.5 : 13.6 (Cmax) and 1 : 5.2 : 17.1 (AUC). The750- mg dose decreased LH concentrations by 16.7% (95% confidence interval 0.5, 30.2). Conclusion Single oral doses of up to 750 mg 8-PN were well tolerated by postmenopausal women. The pharmacokinetic profile of 8-PN was characterized by rapid and probably complete enteral absorption, high metabolic stability, pronounced enterohepatic recirculation and tight dose linearity. The decrease in LH serum concentrations found after the highest dose demonstrates the ability of 8-PN to exert systemic endocrine effects in postmenopausal women. [source] Effectiveness of delayed activated charcoal administration in simulated paracetamol (acetaminophen) overdoseBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 1 2000P. J. A. Yeates Aims,Oral activated charcoal is used to treat drug overdose and is effective at reducing drug absorption when administered within 1 h of drug ingestion. There are fewer data on efficacy when the delay is longer, as is the case in most drug overdoses. This study investigated the efficacy of activated charcoal at preventing paracetamol (acetaminophen) absorption after simulated overdose when administration was delayed between 1 and 4 h. Methods,An open randomized-order four-way crossover study was performed in healthy volunteers comparing the effect of activated charcoal 50 g on the absorption of 3 g paracetamol tablets when administered after an interval of 1, 2 or 4 h or not at all. Plasma paracetamol concentrations were measured over 9 h after paracetamol ingestion using h.p.l.c. and areas under the curve between 4 and 9 h (AUC(4,9 h)) calculated as a measure of paracetamol absorption. Results,Activated charcoal significantly reduced paracetamol AUC(4,9 h)when administered after 1 h (mean reduction 56%; 95% Confidence intervals 34, 78; P<0.002) or 2 h (22%; 6, 39; P<0.03) but not after 4 h (8%; ,8, 24). When administered after 1 h activated charcoal reduced individual plasma paracetamol concentrations significantly at all times between 4 and 9 h after paracetamol administration. Administration at 2 or 4 h had no significant effect. Conclusions,These results in healthy volunteers cannot be extrapolated directly to poisoned patients. However, they provide no evidence of efficacy for activated charcoal when administered after an interval of more than 2 h. [source] Review of select transplant subpopulations at high risk of failure from standard immunosuppressive therapyCLINICAL TRANSPLANTATION, Issue 5 2000Mark H Deierhoi Despite improvements in short-term graft and patient survival rates for solid organ transplants, certain subgroups of transplant recipients experience poorer clinical outcome compared to the general population. Groups including pediatrics, African-Americans, diabetics, cystic fibrosis patients, and pregnant women require special considerations when designing immunosuppressive regimens that optimize transplant outcomes. Problems specific to pediatric transplant recipients include altered pharmacokinetics of immunosuppressive drugs, such as cyclosporine (CsA) and tacrolimus (poor absorption, increased metabolism, rapid clearance), the need to restore growth post-transplantation, and a high incidence of drug-related adverse effects. African-Americans have decreased drug absorption and bioavailability, high immunologic responsiveness, and a high incidence of post-transplant diabetes mellitus. Diabetics and cystic fibrosis patients exhibit poor absorption of immunosuppressive agents, which may lead to underimmunosuppression and subsequent graft rejection. Pregnant women undergo physiologic changes that can alter the pharmacokinetics of immunosuppressives, thus requiring careful clinical management to minimize the risks of either under- or overimmunosuppression to mother and child. To achieve an optimal post-transplant outcome in these high-risk patients, the problems specific to each group must be addressed, and immunosuppressive therapy individualized accordingly. Drug formulation greatly impacts upon pharmacokinetics and the resultant level of immunosuppression. Thus, a formulation with improved absorption (e.g., CsA for microemulsion), higher bioavailability, and less pharmacokinetic variability may facilitate patient management and lead to more favorable outcomes, especially in groups demonstrating low and variable bioavailability. Other strategies aimed at improving transplant outcome include the use of higher immunosuppressive doses, different combinations of immunosuppressive agents, more frequent monitoring, and management of concurrent disease states. [source] | |||||||||||||