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Concentration Vs (concentration + v)
Selected AbstractsThe effect of increased lipoprotein levels on the pharmacokinetics of cyclosporine A in the laboratory ratBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 1 2006Dion R. Brocks Abstract The response of cyclosporine A (CyA) blood concentrations following changes in lipoprotein levels have been inconsistent. Some studies show increases in concentrations, whereas others have shown decreases. The intent of this study was to examine the effect of two rat models of increased lipoprotein on the pharmacokinetics of CyA. One was a simulated high fat content meal, in which 1% cholesterol in peanut oil was administered. The other was the poloxamer 407-induced model of hyperlipidemia. Rats in these two groups were compared to a group fasted overnight before the study. In rats given a simulated high fat meal, at most time points the mean blood and plasma concentrations were lower, though not significantly, compared to fasted animals. Oral lipid led to no significant changes in the measured pharmacokinetic parameters of blood or plasma area under the concentration vs time curve (AUC), clearance (CL), volume of distribution (Vd) or plasma unbound fraction. In the poloxamer 407-treated hyperlipidemic rats there were significant reductions in plasma unbound fraction plasma, Vd and terminal half-life, but not AUC or CL, compared to normolipidemic rats. In contrast, the CL, Vd and t1/2 in the oral lipid-fed rats were all significantly higher than the poloxamer 407 treated animals. Oral absolute bioavailability of CyA was unchanged by oral lipid. In humans and rats the pharmacokinetics of CyA in the face of increased lipoprotein levels do not correspond well to what is typically seen for other drugs that are known to bind to lipoproteins. Copyright © 2005 John Wiley & Sons, Ltd. [source] Pharmacokinetic characterization of a human immunodeficiency virus protease inhibitor, saquinavir, during ethanol intake in ratsBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 8 2003Nobuhito Shibata Abstract Throughout therapeutic drug monitoring of human immunodeficiency virus (HIV) protease inhibitors in HIV-infected patients, it was found that plasma concentrations of saquinavir (SQV) were reduced in patients who had a habit of alcohol intake during double protease therapy with SQV and ritonavir (RTV). This study confirmed the pharmacokinetic profiles of SQV during ethanol intake in rats. After oral administration of SQV alone (20 mg/kg) in rats prepared by free access to 15% ethanol solution for 14 days (day 14 rats), the area under the concentration vs time curves (AUC) showed a significant decrease (p<0.01) in comparison with control rats from 0.78±0.10 to 0.38±0.03 ,g h/ml. For intravenous administration of SQV alone (5 mg/kg) to day 14 rats, the total body clearance increased significantly by 1.4-fold (p<0.05), whereas for intracolonic administration of SQV alone, no significant differences in the values of pharmacokinetic parameters were found between control and day 14 rats. With RTV, which has the strongest inhibitory effect on the CYP3A enzyme of the current HIV protease inhibitors, the AUC values of SQV at RTV doses of 2 and 20 mg/kg in day 14 rats also decreased significantly (p<0.01) from 1.30±0.06 to 0.57±0.05 ,g h/ml and from 17.63±1.66 to 4.18±0.94 ,g h/ml, respectively, indicating that the degree of the decrease of AUC values after oral administration with RTV after ethanol intake was larger than the mono-therapy with SQV. This study showed that ethanol-intake decreases the bioavailability of SQV after oral administration alone or with RTV. These observations provide useful information for the treatment of HIV-infected patients when they receive a combination therapy with SQV and RTV, and arouse attention for the effects of alcohol intake. Copyright © 2003 John Wiley & Sons, Ltd. [source] Amlodipine bioequivalence study: quantification by liquid chromatography coupled to tandem mass spectrometryBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 9 2001M. Carvalho Abstract Objective,To assess the bioequivalence of two amlodipine tablet formulations (Amlodipine® 5 mg tablet from Merck S.A. Indústrias Químicas, Brazil as test formulation and Norvasc® 5 mg tablet from Laboratórios Pfizer Ltd., Brazil as reference formulation) in 24 healthy volunteers of both sexes. Methods,The study was conducted using an open, randomized two-period crossover design with a 4-week washout interval. Plasma samples were obtained over a 144 h period. Plasma amlodipine concentrations were analyzed by combined liquid chromatography coupled to tandem mass spectrometry (LC-MS-MS) with positive ion electrospray ionization using multiple reaction monitoring (MRM). From the amlodipine plasma concentration vs time curves, the following pharmacokinetic parameters were obtained: AUClast, AUC0,inf and Cmax. The statistical interval proposed was 80,125% according to the US Food and Drug Administration Agency. Results,The limit of quantification was 0.1 ng/ml for plasma amlodipine analysis. The geometric mean and the 90% confidence interval (CI) test/reference ratios were 101.2 (92.9,110.2%) for AUClast, 99.6 (91.5,108.4%) for AUC0,inf and 98.5 (89.0,109.1%) for Cmax. Conclusion,Since the 90% CI for AUClast, AUC0,inf and Cmax ratios were within in the 80,125% interval proposed by the US FDA, it was concluded that Amlodipine® 5 mg tablet (test formulation) was bioequivalent to Norvasc® 5 mg tablet, in terms of both rate and extent of absorption. Copyright © 2001 John Wiley & Sons, Ltd. [source] Simultaneous fitting of R- and S-ibuprofen plasma concentrations after oral administration of the racemateBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 4 2001Jörn Lötsch Aims, To assess the pharmacokinetic equivalence of two different formulations of ibuprofen lysinate with special focus on the expected effects. Methods, Sixteen healthy volunteers received cross-over ibuprofen lysinate as either one tablet of 400 mg (,test') or two tablets of 200 mg (,reference'). Ibuprofen plasma concentrations were followed up for 10 h. Bioequivalence was assessed by standard noncompartmental methods. Ibuprofen plasma concentrations were fitted with a model that took bioinversion of R- to S-ibuprofen into account. Results, Peak plasma concentrations of R- and S-ibuprofen were 18.1 and 20 µg ml,1 (test), and 18.2 and 20 µg ml,1 (reference). Areas under the plasma concentration vs time curves were 39.7 and 67.5 µg ml,1 h (test), and 41.1 and 68.2 µg ml,1 h (reference). Clearance of R-ibuprofen was 5.2 (test) and 5 l h,1 (reference). A specific plasma concentration was reached with the test formulation about 5 min later than with the reference. Parameters from compartmental modelling were (given for R-and then for S-ibuprofen): body clearance: 4.9 and 4.64 l h,1, central volume of distribution: 2.8 and 4.1 l, intercompartment clearance: 5.1 and 5.45 l h,1, peripheral volume of distribution: 4.1 and 5.2 l. The absorption rate constant was 1.52 h,1, and the test but not the reference formulation had a lag time of 0.1 h. Simulations showed similarity between formulations of the expected effects except for a calculated delay of 6 min with the test formulation. Conclusions, Ibuprofen formulations were bioequivalent. The pharmacokinetic model may serve as a basis for future pharmacokinetic/pharmacodynamic calculations after administration of racemic ibuprofen. [source] CYP2D6 polymorphism and clinical effect of the antidepressant venlafaxineJOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 5 2006M. E. E. Shams PhD Summary Background:, Venlafaxine (V) is a mixed serotonin and noradrenaline reuptake inhibitor used as a first-line treatment of depressive disorders. It is metabolized primarily by the highly polymorphic cytochrome P450 (CYP) enzyme CYP2D6 to yield a pharmacologically active metabolite, O -desmethylvenlafaxine (ODV), and to a lesser extent by CYP3A4, to yield N -desmethylvenlafaxine (NDV). Objectives:, The aim of this study was to assess whether the O-demethylation phenotype of V has an impact on the pharmacokinetics and clinical outcome. Method:, In 100 patients treated with V, serum concentrations of V, ODV and NDV and the ratios of concentrations ODV/V as a measure of O-demethylation were determined. Individuals exhibiting abnormally high or low metabolic ratios of ODV/V were selected for genotyping. Clinical effects were monitored by the Clinical Global Impressions Scale and side effects by the UKU (Udvalg for Kliniske Undersogelser Side Effect Rating Scale) rating scale. Results:, There was wide inter-individual variability in ODV/V ratios. The median ratio ODV/V was 1·8 and the 10th and 90th percentiles 0·3 and 5·2, respectively. Individuals with ODV/V ratios below 0·3 were all identified as poor metabolizers (PM), with the genotypes *6/*4 (n = 1), *5/*4 (n = 2) or *6/*6 (n = 1). Individuals with ratios above 5·2 were all ultra rapid metabolizers (UM, n = 6) due to gene duplications. Five individuals with intermediate metabolic activity (ODV/V, 1·1 ± 0·8) were heterozygotes with the CYP2D6*4 genotype, and one patient with an intermediate metabolic ratio of 4·8 had the genotype *4/2x*1. Clinical outcome measurements revealed that patients with ODV/V ratios below 0·3 had more side effects (P < 0·005) and reduced serum concentrations of sodium (P < 0·05) in comparison with other patients. Gastrointestinal side effects, notably nausea, vomiting and diarrhoea were the most common. Differences in therapeutic efficacy were not significant between the different phenotypes. Conclusion:, The O-demethylation phenotype of V depends strongly on the CYP2D6 genotype. A PM phenotype of CYP2D6 increases the risk of side effects. [source] | ||||||||||