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First-pass Metabolism (first-pass + metabolism)
Selected AbstractsAlcohol Metabolism: Role in Toxicity and CarcinogenesisALCOHOLISM, Issue 2 2003Thomas M. Badger This article contains the proceedings of a symposium at the 2002 RSA Meeting in San Francisco, organized and co-chaired by Thomas M. Badger, Paul Shih-Jiun Yin, and Helmut Seitz. The presentations were (1) First-pass metabolism of ethanol: Basic and clinical aspects, by Charles Lieber; (2) Intracellular CYP2E1 transport, oxidative stress, cytokine release, and ALD, by Magnus Ingelman-Sundberg; (3) Pulsatile ethanol metabolism in intragastric infusion models: Potential role in toxic outcomes, by Thomas M. Badger and Martin J.J. Ronis; (4) Free radicals, adducts, and autoantibodies resulting from ethanol metabolism: Role in ethanol-associated toxicity, by Emanuele Albano; and (5) Gastrointestinal metabolism of ethanol and its possible role in carcinogenesis, by Helmut Seitz. [source] Non-invasive systemic drug delivery: Developability considerations for alternate routes of administrationJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 1 2010Neil R. Mathias Abstract Over the past few decades alternate routes of administration have gained significant momentum and attention, to complement approved drug products, or enable those that cannot be delivered by the oral or parenteral route. Intranasal, buccal/sublingual, pulmonary, and transdermal routes being the most promising non-invasive systemic delivery options. Considering alternate routes of administration early in the development process may be useful to enable new molecular entities (NME) that have deficiencies (extensive first-pass metabolism, unfavorable physicochemical properties, gastro-intestinal adverse effects) or suboptimal pharmacokinetic profiles that are identified in preclinical studies. This review article describes the various delivery considerations and extraneous factors in developing a strategy to pursue an alternate route of administration for systemic delivery. The various delivery route options are outlined with their pros and cons; key criteria and physicochemical attributes that would make a drug a suitable candidate are discussed; approaches to assess delivery feasibility, toxicity at the site of delivery, and overall developability potential are described; and lastly, product trends and their disease implications are highlighted to underscore treatment precedence that help to build scientific rationale for the pursuit of an alternate route of administration. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:1,20, 2010 [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] Polymeric enhancers of mucosal epithelia permeability: Synthesis, transepithelial penetration-enhancing properties, mechanism of action, safety issuesJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 5 2008Giacomo Di Colo Abstract Transmucosal drug administration across nasal, buccal, and ocular mucosae is noninvasive, eliminates hepatic first-pass metabolism and harsh environmental conditions, allows rapid onset, and further, mucosal surfaces are readily accessible. Generally, however, hydrophilic drugs, such as peptides and proteins, are poorly permeable across the epithelium, which results in insufficient bioavailability. Therefore, reversible modifications of epithelial barrier structure by permeation enhancers are required. Low molecular weight enhancers generally have physicochemical characteristics favoring their own absorption, whereas polymeric enhancers are not absorbed, and this minimizes the risk of systemic toxicity. The above considerations have warranted the present survey of the studies on polymeric transmucosal penetration-enhancers that have appeared in the literature during the last decade. Studies on intestinal permeation enhancers are also reviewed as they give information on the mechanism of action and safety of polymers. The synthesis and characterization of polymers, their effectiveness in enhancing the absorption of different drugs across different epithelium types, their mechanism of action and structure-efficacy relationship, and the relevant safety issues are reviewed. The active polymers are classified into: polycations (chitosan and its quaternary ammonium derivatives, poly- L -arginine (poly- L -Arg), aminated gelatin), polyanions (N-carboxymethyl chitosan, poly(acrylic acid)), and thiolated polymers (carboxymethyl cellulose-cysteine, polycarbophil (PCP)-cysteine, chitosan-thiobutylamidine, chitosan-thioglycolic acid, chitosan-glutathione conjugates). © 2007 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 97: 1652,1680, 2008 [source] Contribution of Gastric Oxidation to Ethanol First Pass Metabolism in BaboonsALCOHOLISM, Issue 7 2000Enrique Baraona Background: A portion of ingested alcohol does not reach the systemic blood, undergoing a first-pass metabolism (FPM) during gastric and hepatic circulation. Methods: To determine whether the stomach can metabolize sufficient ethanol to account for the FPM, and to what extent gastric alcohol dehydrogenase (ADH) activity is responsible, the hepatic vein, the portal vein, and the aorta were cannulated nonocclusively in baboons to measure the conversion of ethanol to acetate in vivo. 14C-ethanol (300 mg/kg as a 15% solution) was given intragastrically (IG) whereas 3Hacetate was continuously infused intravenously (IV).14C-acetate was measured after exhaustive evaporation of ethanol. Simultaneous sampling of hepaticvenous, portal and arterial blood was carried out for 3 hr, at the end of which the same alcohol dose was given IV to calculate the Michaelis-Menten parameters of elimination. Results: Analysis of the IV and IG ethanol curves revealed a FPM of 94 ± 11 mg/kg (31% of dose). The portal-arterial differences were negative for 3H-acetate (indicating net extraction) and positive for 14Cethanol and 14C-acetate (indicating net output). Portal acetate production (extraction plus net output multiplied by the portal plasma flow) increased with time and accounted, over the first 3 hr (82 ± 13 mg/kg), for 87% of the FPM. Alcohol oxidation by gastric ADH activity (28.7 ± 7.2 mg/kg) accounted for only 31% of the FPM. Conclusions: The in vivo oxidation of ethanol to acetate in the upper digestive tract accounts for the FPM of ethanol and is mediated, at least in part, by ADH activity. [source] Effects of Sairei-to on the pharmacokinetics of nifedipine in ratsPHYTOTHERAPY RESEARCH, Issue 1 2008Mika Ikehata Abstract Sairei-to is a traditional herbal medicine used to complement, and as an alternative to, Western drugs. The aim of this study was to evaluate the pharmacokinetic interactions between Sairei-to and nifedipine (NFP), a substrate for CYP3A, in rats. NFP-oxidizing activity and the pharmacokinetics of NFP were examined after a single or 1-week of administration of Sairei-to (EK-114). NFP-oxidizing activity was enhanced transiently around 24 h after a single administration of EK-114 (1400 mg/kg). In vivo, the first-pass metabolism of NFP increased in the small intestine at 24 h after the administration of EK-114, and this effect disappeared at 72 h. Co-administration of EK-114 tended to inhibit the metabolism of NFP. On the other hand, when EK-114 was given at a high dose (1400 mg/kg) for 1 week, the oxidation of NFP in the small intestine was inhibited, and Cmax and AUC after the oral administration of NFP increased. In addition, a clinical dose of EK-114 (140 mg/kg) did not alter the pharmacokinetics of NFP, regardless of the administration schedule. EK-114 was suggested to affect the metabolism of NFP. However, the CYP3A-mediated pharmacokinetic interaction on the concomitant use of EK-114 may not be clinically significant. Copyright © 2007 John Wiley & Sons, Ltd. [source] Grapefruit Juice Enhances the Exposure to Oral OxycodoneBASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 4 2010Tuija H. Nieminen The objective of this study was to examine the effect of grapefruit juice on the pharmacokinetics and pharmacodynamics of oral oxycodone in a randomized cross-over study with two phases at an interval of 4 weeks. Twelve healthy volunteers ingested 200 ml of grapefruit juice or water t.i.d. for 5 days. An oral dose of oxycodone hydrochloride 10 mg was administered on day 4. Oxycodone, noroxycodone, oxymorphone and noroxymorphone concentrations were analysed from the plasma samples for 48 hr and behavioural and analgesic effects were recorded for 12 hr. Grapefruit juice increased the mean area under the oxycodone concentration,time curve (AUC0,,) by 1.7-fold (p < 0.001), the peak plasma concentration by 1.5-fold (p < 0.001) and the half-life of oxycodone by 1.2-fold (p < 0.001) as compared to the water. The metabolite-to-parent AUC0,, ratios (AUCm/AUCp) of noroxycodone and noroxymorphone decreased by 44% (p < 0.001) and 45% (p < 0.001), respectively. Oxymorphone AUC0,, increased by 1.6-fold (p < 0.01) after grapefruit juice, but the AUCm/AUCp remained unchanged. Pharmacodynamic changes were modest and only self-reported performance significantly impaired after grapefruit juice. Analgesic effects were not influenced. Grapefruit juice inhibited the CYP3A4-mediated first-pass metabolism of oxycodone, decreased the formation of noroxycodone and noroxymorphone and increased that of oxymorphone. We conclude that dietary consumption of grapefruit products may increase the concentrations and effects of oxycodone in clinical use. [source] Quantitative LC/MS/MS method and in vivo pharmacokinetic studies of vitexin rhamnoside, a bioactive constituent on cardiovascular system from hawthornBIOMEDICAL CHROMATOGRAPHY, Issue 4 2007Mingjin Liang Abstract A simple and accurate liquid chromatography coupled with tandem mass spectrometry method was developed for determination and in vivo pharmacokinetic studies of vitexin rhamnoside in rat plasma. After protein precipitation using methanol, the analytes were separated by a Luna C18 column with an isocratic elution and analyzed by mass spectrometry in multiple reaction monitoring mode using the respective negative ion at m/z 577.2,293.0 for vitexin rhamnoside and m/z 593.2,413.0 for internal standard (IS) vitexin glucoside. The method was validated systematically within the concentration range 5,5000 µg/L (R > 0.996) and the lower limit of quantitation was 5 µg/L. Acceptable precision and accuracy were acquired for concentrations over the standard curve range. It was further applied to assess pharmacokinetics and bioavailability of vitexin rhamnoside after intravenous and oral administration to rats. The oral bioavailability of vitexin rhamnoside was only 3.57%, which indicated that vitexin rhamnoside had poor absorption or underwent extensive first-pass metabolism. Practical utility of this new LC/MS/MS method was confirmed in pilot pharmacokinetic studies in rats following both intravenous and oral administration. Copyright © 2007 John Wiley & Sons, Ltd. [source] Metabolism, oral bioavailability and pharmacokinetics of chemopreventive kaempferol in ratsBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 7 2009Avantika Barve Abstract The purpose of this study was to compare the hepatic and small intestinal metabolism, and to examine bioavailability and gastro-intestinal first-pass effects, of kaempferol in rats. Liver and small intestinal microsomes fortified with either NADPH or UDPGA were incubated with varying concentrations of kaempferol for up to 120,min. Based on the values of the kinetic constants (Km and Vmax), the propensity for UDPGA-dependent conjugation compared with NADPH-dependent oxidative metabolism was higher for both hepatic and small intestinal microsomes. Male Sprague-Dawley rats were administered kaempferol intravenously (i.v.) (10, 25,mg/kg) or orally (100, 250,mg/kg). Gastro-intestinal first-pass effects were observed by collecting portal blood after oral administration of 100,mg/kg kaempferol. Pharmacokinetic parameters were obtained by non-compartmental analysis using WinNonlin. After i.v. administration, the plasma concentration,time profiles for 10 and 25,mg/kg were consistent with high clearance (,3,L/hr/kg) and large volumes of distribution (8,12,L/hr/kg). The disposition was characterized by a terminal half-life value of 3,4,h. After oral administration the plasma concentration,time profiles demonstrated fairly rapid absorption (tmax,1,2,h). The area under the curve (AUC) values after i.v. and oral doses increased approximately proportional to the dose. The bioavailability (F) was poor at ,2%. Analysis of portal plasma after oral administration revealed low to moderate absorption. Taken together, the low F of kaempferol is attributed in part to extensive first-pass metabolism by glucuronidation and other metabolic pathways in the gut and in the liver. Copyright © 2009 John Wiley & Sons, Ltd. [source] Dose-dependent pharmacokinetics of a new Na+/H+ exchanger inhibitor KR-33028 in ratsBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 8 2007Young Hoon Kim Abstract The dose-dependency of the pharmacokinetics of a new Na+/H+ exchanger inhibitor, KR-33028 was evaluated in rats after intravenous and oral administration. After intravenous administration of KR-33028 (1, 5, 10 and 20mg/kg doses), the systemic clearance (Cl) was reduced and AUC was nonlinearly increased as a function of dose. The volume of distribution (Vss), however, remained unchanged as the dose was increased, which was consistent with unaltered plasma protein binding in vitro (unbound fraction = 0.09,0.12). Upon oral administration (2, 10 and 20mg/kg doses), KR-33028 was rapidly absorbed, and this was consistent with high Caco-2 Papp values found in vitro. There were nonlinear increases in AUC and Cmax, and the absolute oral bioavailability (F) was significantly increased as the dose was increased (F = 23.3%, 40.7% and 78.2% for 2, 10 and 20mg/kg doses, respectively). The extent of urinary excretion was low for both intravenous (0.5,0.7%) and oral (0.2,0.8%) doses. The reduced systemic clearance and increased oral bioavailability at high doses appears to be due to a saturable first-pass metabolism. Copyright © 2007 John Wiley & Sons, Ltd. [source] Minimal effect of ketoconazole on cyclosporine (SangCyATM) oral absorption and first-pass metabolism in rats: evidence of a significant vehicle effect on SangCyA absorptionBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 2 2002Susan Wong Abstract The current work evaluated the effect of the CYP3A inhibitor ketoconazole on the oral absorption and first-pass metabolism of cyclosporine administered as the SangCyA formulation. Groups of 6 male Sprague,Dawley rats were administered SangCyA (5 and 15 mg/kg) by oral gavage alone and with ketoconazole (30 mg/kg). Blood cyclosporine levels were measured over 6 h, encompassing the cyclosporine absorption window. A significant vehicle effect on SangCyA absorption was observed. Comparing a 15 mg/kg dose, cyclosporine Cmax (mean±SD 1.12±0.16 µg/ml) and AUC0,6 (5.34±0.71 µg h/ml) were 50% lower when propylene glycol was used as gavage vehicle instead of saline (2.19±0.94 µg/ml and 9.52±2.52 µg h/ml, respectively). Coefficients-of-variation for these parameters were halved in the propylene glycol vehicle however Tmax was unaffected. Ketoconazole increased cyclosporine Cmax and AUC0,6 by 50,60%, regardless of the vehicle or the cyclosporine dose, without altering Tmax (2,3 h). The small effect of ketoconazole suggests that CYP3A-mediated intestinal and first-pass hepatic metabolism are minor determinants of cyclosporine oral bioavailability in rats. Copyright © 2002 John Wiley & Sons, Ltd. [source] Maximizing anticholinergic therapy for overactive bladder: has the ceiling been reached?BJU INTERNATIONAL, Issue 2007Scott A. MacDiarmid SUMMARY Urinary incontinence affects an estimated 20,33% of adults the USA and 55% of the country's elderly [1], having a more substantial impact on the physical and mental dimension of quality of life than other common chronic diseases. Muscarinic receptor antagonists, including oxybutynin, tolterodine, trospium chloride, darifenacin, and solifenacin, are front-line therapies for overactive bladder (OAB), with an efficacy of 65,75% in reducing major symptoms. Strategies to increase the therapeutic index have included behavioural therapy, flexible dosing, and dose escalation, as well as newer formulations that reduce anticholinergic side-effects. Among approved OAB agents, the oxybutynin transdermal-delivery system has been associated with a lower incidence of dry mouth than immediate- and extended-release formulations of traditional agents. With a low propensity for drug interactions and dry mouth, it is a likely candidate for older patients taking multiple medications. The transdermal patch bypasses systemic and first-pass metabolism, avoiding higher plasma concentrations of the active metabolite (N -desethyloxybutynin) thought to be associated with dry mouth symptoms. Anticholinergics have a significant role to play in the management of OAB; newer drugs targeted toward muscarinic receptors, and novel delivery systems, continue to increase the therapeutic index for this condition. [source] Stereoselective binding of human serum albuminCHIRALITY, Issue 3 2006Victor Tuan Giam Chuang Abstract Stereoselectivity in binding can have a significant effect on the drug disposition such as first-pass metabolism, metabolic clearance, renal clearance, and protein and tissue binding. Human serum albumin (HSA) is able to stereoselectively bind a great number of various endogenous and exogenous compounds. Various experimental data suggested that the two major drug-binding cavities, namely, site I and site II, do not seem to be the stereoselective binding sites of HSA. Stereoselective binding of HSA under disease conditions such as renal and hepatic diseases was found to be enhanced. In addition, site-to-site displacement of a site II-specific drug by another site II-specific drug was found to be stereoselective, too. Endogenous compounds such as long-chain fatty acids and uremic toxins are likely to cause combined direct and cascade effects that contribute to the preferential binding of a particular drug enantiomer. Taking together the findings of other studies, it is highly possible that the stereoselective binding site exists at the interface of the subdomains. © 2006 Wiley-Liss, Inc. Chirality [source] Stereoselective pharmacokinetics of clausenamide enantiomers and their major metabolites after single intravenous and oral administration to ratsCHIRALITY, Issue 8 2003Chuan Jiang Zhu Abstract The pharmacokinetics of clausenamide (CLA) enantiomers and their metabolites were investigated in Wistar rat. After intravenous and oral administration at a dose of 80 and 160 mg/kg each enantiomer, plasma concentrations of (,)- or (+)-CLA and its major metabolites were simultaneously determined by reverse-phase HPLC with UV detection. Notably, stereoselective differences in pharmacokinetics were found. The mean plasma levels of (+)-CLA were higher at almost all time points than those of (,)-CLA. (+)-CLA also exhibited greater tmax, Cmax, t1/2,, AUC0,12h, and AUC0,, and smaller CL (or CL/F) and Vd (or Vd/F), than its antipode. The (+)/(,) isomer ratios for t1/2,, tmax, AUC0,12 h, and AUC0,,, which ranged from 1.26 to 2.08. The ratio for CL (or CL/F) was about 0.5, and there were significant differences in these values between CLA enantiomers (P < 0.05), implying that the absorption, distribution, and elimination of (,)-CLA were more rapid than those of (+)-CLA. Similar findings for (,)-7-OH-CLA, the major metabolite of (,)-CLA, and (+)-4-OH-CLA, the major metabolite of (+)-CLA, can be also seen in rat plasma. The contributing factors for the differences in stereoselective pharmacokinetics of CLA enantiomers appeared to be involved in their different plasma protein binding, first-pass metabolism and interaction with CYP enzymes, especially with their metabolizing enzyme CYP 3A isoforms. Chirality 15:668,673, 2003. © 2003 Wiley-Liss, Inc. [source] | |||||||||||||