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Drug Pharmacokinetics (drug + pharmacokinetic)
Selected AbstractsHyperthermic intraoperative intraperitoneal chemotherapy with cisplatin and doxorubicin in patients who undergo cytoreductive surgery for peritoneal carcinomatosis and sarcomatosisCANCER, Issue 2 2002Phase I study Abstract BACKGROUND Hyperthermic intraperitoneal intraoperative chemotherapy (HIIC) combined with cytoreductive surgery (CS) has been proposed as a new multimodal treatment mainly for carcinomatosis of gastrointestinal origin. To evaluate whether this regimen could be used for other tumor types, the authors conducted a Phase I study on HIIC with doxorubicin and cisplatin in patients with peritoneal carcinomatosis or sarcomatosis. PATIENTS AND METHODS Thirty-one patients with peritoneal carcinomatosis or sarcomatosis (PCS) were enrolled for the study. After completion of CS, HIIC was administered with drug doses that were increased for each consecutive cohort following a three-patient cohort scheme. Thereafter, the accrual was stopped when Grade 4 locoregional or systemic toxicity was observed. The maximum tolerated dose (MTD) was considered the dose in the previous triplet. Drug pharmacokinetics and procedure costs also were analyzed. RESULTS After CS, residual tumors were not present or measured less than or equal to 3 mm (in dimension) in all cases. Maximum tolerated dose was 15.25 and 43.00 mg L,1 for doxorubicin and cisplatin, respectively. The perfusate/plasma area under the curve ratios were favorable for both drugs, at 162 ± 113 and 20.6 ± 6.0, respectively, for doxorubicin and cisplatin. Doxorubicin levels in the peritoneum were higher than in tumor or normal tissue samples. There were no postoperative deaths. Surgery-related complications were observed in 25% of cases. Findings at cost analysis showed that the length of stay in the operation room and intensive care unit were the major cost drivers. CONCLUSIONS Cytoreductive surgery combined with HIIC is an expensive but feasible therapeutic approach for locally advanced abdominal tumors. Because our preliminary findings for local disease control are encouraging, a Phase II study is now advisable to verify the activity of this promising treatment. Cancer 2002;94:492,9. © 2002 American Cancer Society. [source] Review article: Low-molecular-weight heparin as an alternative anticoagulant to unfractionated heparin for routine outpatient haemodialysis treatmentsNEPHROLOGY, Issue 5 2009ANDREW DAVENPORT SUMMARY Unfractionated heparin is currently the most widely used anticoagulant for outpatient haemodialysis. However, unfractionated heparin is a series of molecules, and as such has variable pharmacodynamics. Low-molecular-weight heparins were developed to improve both drug pharmacokinetic and dynamics, so to provide a reliable predictable clinical effect. The low-molecular-weight heparins are potent agents, but have an increased half-life compared with unfractionated heparin, and also require specialist laboratory monitoring. Despite these apparent drawbacks, low-molecular-weight heparins have become the anticoagulants of choice in Western Europe for routine outpatient haemodialysis sessions, due to the reliability of their clinical effect, and ease of administration, coupled with cost reduction. In standard clinical practice laboratory monitoring is not routinely performed, with drug dosing assessed by clinical inspection of the extracorporeal circuit, and the time for fistula needle sites to stop bleeding. [source] Determination of ABCB1 polymorphisms and haplotypes frequencies in a French populationFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 4 2007Elise Jeannesson Abstract The ATP-binding cassette (ABC) transporter ABCB1, or P-glycoprotein, is a transmembrane efflux pump well known for its implication in drug transport and chemoresistance. ABCB1 substrates include either drugs, such as antiretrovirals and immunomodulators, or physiological molecules like phospholipids. Pharmacogenetic analysis of ABCB1 polymorphisms, in addition to other xenobiotic metabolizing enzymes, might help to personalize and optimize drug therapy. Indeed, some polymorphisms of ABCB1 have been implicated in susceptibility to diseases, changes in drug pharmacokinetics, and in variation of the biological response to drug treatment. In addition, variant and haplotype distributions differ depending on ethnicity. Thus, some ethnies may be at higher risk for adverse events, inefficacy of treatment or prevalence of pathologies. This study aimed to determine frequencies of ABCB1 polymorphisms and haplotypes in a sample of French healthy individuals. DNA was isolated from blood-EDTA. Polymerase chain reaction-restriction fragment length polymorphism and TaqMan single nucleotide polymorphism genotyping assays were used to genotype 227 individuals for T-129C, G-1A, A61G, G1199A, C1236T, T-76A, G2677T/A and C3435T polymorphisms. The observed frequencies of the variant allele for these eight polymorphisms are 0.04, 0.08, 0.09, 0.06, 0.42, 0.46, 0.45 and 0.46 respectively. These polymorphisms are in linkage disequilibrium and haplotype frequencies were determined, the most frequent haplotype being the one with variants at position 1236, 2677 and 3435 and wild-type alleles at the other positions. Finally, the frequencies of these eight ABCB1 polymorphisms in our French individuals supposed to be healthy population are quite similar to those described in other Caucasian populations except for the C3435T polymorphism. [source] Consideration of the linear concentration increase of the unbound drug fraction in plasmaJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 2 2009Leonid M. Berezhkovskiy Abstract The concentration of drug in plasma may not necessarily be much less than that of the drug binding proteins, as often considered. Thus the unbound drug fraction could be concentration dependent, which should be taken into account in the interpretation of drug pharmacokinetics and modeling. It is shown that the increase of the unbound drug fraction, fu, can be very accurately considered proportional to the drug plasma concentration for a relatively wide range of concentrations. Equations for the calculation of fu in this linear range are obtained, as well the limiting drug concentration when the linear approximation of fu is applicable. The suggested approach greatly simplifies the calculation of fu and can be ready used in pharmacokinetic calculations and PK-PD models, as well as for the prediction of the change of fu due to the variation of protein concentrations in plasma. Naproxen protein binding in human plasma is considered as an illustration of the method. © 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:383,393, 2009 [source] Pharmacokinetics of drugs in rats with diabetes mellitus induced by alloxan or streptozocin: comparison with those in patients with type I diabetes mellitusJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 1 2010Joo H. Lee Abstract Objectives In rats with diabetes mellitus induced by alloxan (DMIA) or streptozocin (DMIS), changes in the cytochrome P450 (CYP) isozymes in the liver, lung, kidney, intestine, brain, and testis have been reported based on Western blot analysis, Northern blot analysis, and various enzyme activities. Changes in phase II enzyme activities have been reported also. Hence, in this review, changes in the pharmacokinetics of drugs that were mainly conjugated and metabolized via CYPs or phase II isozymes in rats with DMIA or DMIS, as reported in various literature, have been explained. The changes in the pharmacokinetics of drugs that were mainly conjugated and mainly metabolized in the kidney, and that were excreted mainly via the kidney or bile in DMIA or DMIS rats were reviewed also. For drugs mainly metabolized via hepatic CYP isozymes, the changes in the total area under the plasma concentration,time curve from time zero to time infinity (AUC) of metabolites, AUCmetabolite/AUCparent drug ratios, or the time-averaged nonrenal and total body clearances (CLNR and CL, respectively) of parent drugs as reported in the literature have been compared. Key findings After intravenous administration of drugs that were mainly metabolized via hepatic CYP isozymes, their hepatic clearances were found to be dependent on the in-vitro hepatic intrinsic clearance (CLint) for the disappearance of the parent drug (or in the formation of the metabolite), the free fractions of the drugs in the plasma, or the hepatic blood flow rate depending on their hepatic extraction ratios. The changes in the pharmacokinetics of drugs that were mainly conjugated and mainly metabolized via the kidney in DMIA or DMIS rats were dependent on the drugs. However, the biliary or renal CL values of drugs that were mainly excreted via the kidney or bile in DMIA or DMIS rats were faster. Summary Pharmacokinetic studies of drugs in patients with type I diabetes mellitus were scarce. Moreover, similar and different results for drug pharmacokinetics were obtained between diabetic rats and patients with type I diabetes mellitus. Thus, present experimental rat data should be extrapolated carefully in humans. [source] Cloning and heterologous expression of the ovine (Ovis aries) P-glycoprotein (Mdr1) in Madin,Darby canine kidney (MDCK) cellsJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 3 2010D. ZAHNER Zahner, D., Alber, J., Petzinger, E. Cloning and heterologous expression of the ovine (Ovis aries) P-glycoprotein (Mdr1) in Madin,Darby canine kidney (MDCK) cells. J. vet. Pharmacol. Therap.33, 304,311. P-glycoprotein (P-gp) plays a crucial role in the multidrug resistance of pathogenic helminths in sheep (Ovis aries) as well as in antiparasitic drug pharmacokinetics in the host. We cloned sheep P-gp cDNA and expressed it stably in Madin,Darby canine kidney (MDCK) cells. The open reading frame consists of 3858 nucleotides coding for a 1285 amino acids containing protein. The sequence shows high homology to the orthologs of other mammalian species, especially cattle. Both ruminant DNA sequences show a 9 bp insertion that is lacking in all other investigated sequences. Expressed in MDCK cells, the protein displays a size of 170 kDa on Western analysis. Transfection of MDCK cells with sheep P-gp resulted in 10- to 50-fold resistance to the cytotoxic P-gp substrates colchicin and daunorubicin, and in reduced digoxin accumulation. [source] Therapeutic implications of the MDR-1 geneJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 5 2004K. L. Mealey Drug transporters significantly influence drug pharmacokinetics and pharmacodynamics. P-glycoprotein (P-gp), the product of the MDR1 (ABCB1) gene, is among the most well-characterized drug transporters, particularly in veterinary medicine. A number of clinically relevant, structurally and functionally unrelated drugs are substrates for P-gp. P-gp is expressed by a variety of normal tissues including the intestines, renal tubular cells, brain capillary endothelial cells, biliary canalicular cells, and others, where it functions to actively extrude substrate drugs. In this capacity, P-gp limits oral absorption and central nervous system entry of many substrate drugs. A number of MDR1 polymorphisms have been described in human patients, some of which result in altered drug pharmacokinetics and susceptibility to diseases such as Parkinson's disease, inflammatory bowel disease, refractory seizures, and others. An MDR1 polymorphism in herding breed dogs, including collies and Australian shepherds, has been demonstrated to be the cause of ivermectin sensitivity in these breeds. Recent evidence suggests that this polymorphism, a 4-bp deletion mutation, results in increased susceptibility to the toxicity of several drugs in addition to ivermectin. Furthermore, data in rodent models suggest that P-gp may play an important role in regulating the hypothalamic,pituitary,adrenal axis. [source] Pharmacogenetics of Immunosuppressants: Progress, Pitfalls and PromisesAMERICAN JOURNAL OF TRANSPLANTATION, Issue 7 2008D. Cattaneo Most of the immunosuppressants used in organ transplantation are characterized by a narrow therapeutic index, whereby underdosing is associated with increased risk of rejection episodes and overdosing may exacerbate drug-related toxicity. Pharmacogenetics,complementary to pharmacokinetics,holds the potential to allow individualized dosing of immunosuppressive agents to optimize their therapeutic actions while minimizing adverse effects. Most of the studies have focused on polymorphisms of genes involved in drug metabolism and distribution, but as of now, only thiopurine-S-methyltransferase and cytochrome P 450 3A5 genotypes appear to have sufficiently large influence to have potentialities in guiding drug dosing. This may reflect the fact that available information from other polymorphisms derives almost exclusively from retrospective observations or from studies with important methodological biases. Active investigations aimed at identifying allelic variants of gene encoding for the pharmacologic targets are now ongoing. Recent studies have demonstrated that also donor genotype may play a significant role in immunosuppressive drug pharmacokinetics and pharmacodynamics. As one of the main future tasks, it is mandatory to develop mathematical models able to incorporate multiple gene polymorphisms with pharmacokinetic data and other critical information, providing algorithms able to individualize the best immunosuppressive therapy for each patient before transplantation. [source] Patient variation in veterinary medicine: part I. Influence of altered physiological statesJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 3 2010M. MARTINEZ Martinez, M., Modric, S. Patient variation in veterinary medicine: part I. Influence of altered physiological states. J. vet. Pharmacol. Therap.33, 213,226. In veterinary medicine, the characterization of a drug's pharmacokinetic (PK) properties is generally based upon data that are derived from studies that employ small groups of young healthy animals, often of a single breed. These are also the data from which population predictions are often generated to forecast drug exposure characteristics in the target population under clinical conditions of use. In veterinary medicine, it is rare to find information on the covariates that can influence drug exposure characteristics. Therefore, it is important to recognize some of the factors that can alter the outcome of PK studies and therefore potentially alter the pharmacological response. Some of these factors are easily identified, such as breed, gender, age, and body weight. Others are less obvious, such as disease, heritable traits, and environmental factors. This manuscript provides an overview of the various stressors (such as disease, inflammation, pregnancy, and lactation) that can substantially alter drug PK. Part II of this series provides an overview of the potential impact of physiological variables such as age, weight, and heritable traits, on drug PK. Ultimately, failure to identify appropriate covariates can lead to substantial error when predicting the dose,exposure relationship within a population. [source] Itraconazole vs. fluconazole for antifungal prophylaxis in allogeneic stem-cell transplant patientsCLINICAL MICROBIOLOGY AND INFECTION, Issue 2006D. J. Winston Abstract Results from randomised, controlled trials and routine clinical experience indicate that itraconazole can be more effective than fluconazole for prevention of invasive fungal infections in allogeneic stem-cell transplant patients. The effective and safe use of prophylactic itraconazole requires an appreciation of the drug's pharmacokinetics, the optimal dosing regimen, and potential drug interactions. Because of the erratic bioavailability of oral itraconazole capsules, only the intravenous (200 mg once-daily) and oral cyclodextrin solution (200 mg twice-daily) formulations of the drug should be used. Prophylaxis should be started after the completion of pre-transplant chemotherapy in order to avoid interactions with chemotherapeutic agents. Patients unable to tolerate oral itraconazole should be given intravenous itraconazole to maintain effective prophylaxis. Post-transplant interactions between itraconazole and immunosuppressive agents or other drugs are generally not problematic, can be easily managed, and need not limit the use of itraconazole. If these guidelines are followed, Aspergillus and other invasive fungal infections can be safely prevented in allogeneic stem-cell transplant patients. [source] Effects of induced hyperthermia on pharmacokinetics of ropivacaine in ratsFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 4 2010Romain Guilhaumou Abstract Ropivacaine is a local anaesthetic used for epidural anaesthesia and postoperative pain relief. Hyperthermia is a very common sign of infection associated with variations in physiological parameters, which may influence drugs pharmacokinetics. The aim of this study was to determine the effects of induced hyperthermia on ropivacaine pharmacokinetics in rats. Two groups of six rats were given a single subcutaneous ropivacaine injection. Hyperthermia-induced animals were placed in a water bath to obtain a stable mean core temperature of 39.7 °C. After blood samples collection, ropivacaine serum concentrations and pharmacokinetic parameters were determined. Two other groups of six rats were sacrificed 30 min after ropivacaine injection to determine serum and tissues (brain and heart) concentrations. Our results (median ± inter quartile range) reveal a significant increase of the total apparent clearance (0.0151 ± 0.000800 L/min vs. 0.0134 ± 0.00134 L/min), apparent volume of distribution (Vd) (2.19 ± 0.27 L vs. 1.57 ± 0.73 L) and a significant decrease in exposure (488 ± 50.6 mg.min/L vs. 572 ± 110 mg.min/L) in induced-hyperthermia group. We observed a significant increase in brain ropivacaine concentration in hyperthermic rats (8.39 ± 8.42 ,g/g vs. 3.48 ± 3.26 ,g/g) and no significant difference between cardiac concentrations in the two groups (5.38 ± 4.83 ,g/g vs. 3.73 ± 2.44 ,g/g). Results suggest a higher tissular distribution of ropivacaine and an increase in blood,brain barrier permeability during hyperthermia. The hyperthermia-induced increase in Vd could be responsible for an increase in cerebral ropivacaine toxicity. These experimental data provide a basis for future clinical investigations in relation to local anaesthetic use in hyperthermic patients. 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