AIMS
This study aimed to investigate possible effects of ABCB1 genotype on fluvastatin, pravastatin, lovastatin, and rosuvastatin pharmacokinetics.METHODS
In a fixed-order crossover study, 10 healthy volunteers with the ABCB1 c.1236C/C-c.2677G/G-c.3435C/C (CGC/CGC) genotype and 10 with the c.1236T/T-c.2677T/T-c.3435T/T (TTT/TTT) genotype ingested a single 20-mg dose of fluvastatin, pravastatin, lovastatin, and rosuvastatin. Plasma fluvastatin, pravastatin, and lovastatin concentrations were measured up to 12 h and plasma and urine rosuvastatin concentrations up to 48 and 24 h, respectively.RESULTS
The ABCB1 genotype had no significant effect on the pharmacokinetics of any of the investigated statins. The geometric mean ratio (95% confidence interval) of the area under the plasma concentration–time curve from 0 h to infinity (AUC0–∞) in participants with the TTT/TTT genotype to that in those with the CGC/CGC genotype was 0.96 (0.77, 1.20; P= 0.737) for fluvastatin, 0.92 (0.53, 1.62; P= 0.772) for pravastatin, 0.83 (0.36, 1.90; P= 0.644) for lovastatin, 1.25 (0.72, 2.17; P= 0.400) for lovastatin acid, and 1.10 (0.73, 1.65; P= 0.626) for rosuvastatin. The AUC0–∞ of lovastatin acid correlated significantly with that of rosuvastatin (r= 0.570, P= 0.009), but none of the other AUC0–∞ pairs showed a significant correlation.CONCLUSIONS
These data suggest that the ABCB1 c.1236C-c.2677G-c.3435C and c.1236T-c.2677T-c.3435T haplotypes play no significant role in the interindividual variability in the pharmacokinetics of fluvastatin, pravastatin, lovastatin, and rosuvastatin. 相似文献AIMS
To assess the association between polymorphisms of the ABCB1 gene and the pharmacokinetics of verapamil among healthy Chinese Han ethnic subjects.METHODS
Based on polymorphisms of the ABCB1 gene at positions 2677 and 3435, 24 healthy male participants were divided into three groups: 2677GG/3435CC (n = 6), 2677GT/3435CT (n = 12) and 2677TT/3435TT (n = 6). Each subject had received a single oral dose of verapamil (80 mg) under fasting conditions. Multiple blood samples were collected over 24 h, and plasma concentrations of verapamil were determined by HPLC. Pharmacokinetic characteristics were compared between the different genotypic groups.RESULTS
The pharmacokinetics parameters of verapamil differed significantly among the three genotypic groups. AUC(last) was significantly lower among individuals with the 2677TT/3435TT (159.5 ± 79.0 ng ml−1 h) and 2677GT/3435CT (189.3 ± 73.1 ng ml−1 h) genotypes than those with the 2677GG/3435CC genotype (303.1 ± 83.7 ng ml−1 h) (P= 0.004 and P= 0.008, respectively). However, the CL/F value was higher among subjects with the 2677TT/3435TT (523.0 ± 173.7 l h−1) genotype than those with the 2677GT/3435CT (452.2 ± 188.6 l h−1) or 2677GG/3435CC (265.4 ± 72.8 l h−1) genotypes. A significant difference was also found between the latter two groups (P= 0.034). In addition, the Cmax tended to be higher among subjects with the 2677GG/3435CC genotype than those with the 2677GT/3435CT or 2677TT/3435TT genotypes (42.2 ± 3.9 vs 32.2 ± 16.2 vs 38.1 ± 13.7 ng ml−1).CONCLUSIONS
Our study showed for the first time that verapamil pharmacokinetics may be influenced by particular genetic polymorphisms of the ABCB1 gene among healthy Chinese Han ethnic subjects. An individualized dosage regimen design incorporating such information may improve the efficacy of the drug whilst reducing adverse reactions. 相似文献Background and purpose:
Lopinavir is extensively metabolized by cytochrome P450 3A (CYP3A) and is considered to be a substrate for the drug transporters ABCB1 (P-glycoprotein) and ABCC2 (MRP2). Here, we have assessed the individual and combined effects of CYP3A, ABCB1 and ABCC2 on the pharmacokinetics of lopinavir and the relative importance of intestinal and hepatic metabolism. We also evaluated whether ritonavir increases lopinavir oral bioavailability by inhibition of CYP3A, ABCB1 and/or ABCC2.Experimental approach:
Lopinavir transport was measured in Madin-Darby canine kidney cells expressing ABCB1 or ABCC2. Oral lopinavir kinetics (+/− ritonavir) was studied in mice with genetic deletions of Cyp3a, Abcb1a/b and/or Abcc2, or in transgenic mice expressing human CYP3A4 exclusively in the liver and/or intestine.Key results:
Lopinavir was transported by ABCB1 but not by ABCC2 in vitro. Lopinavir area under the plasma concentration – time curve (AUC)oral was increased in Abcb1a/b−/− mice (approximately ninefold vs. wild-type) but not in Abcc2−/− mice. Increased lopinavir AUCoral (>2000-fold) was observed in cytochrome P450 3A knockout (Cyp3a−/−) mice compared with wild-type mice. No difference in AUCoral between Cyp3a−/− and Cyp3a/Abcb1a/b/Abcc2−/− mice was observed. CYP3A4 activity in intestine or liver, separately, reduced lopinavir AUCoral (>100-fold), compared with Cyp3a−/− mice. Ritonavir markedly increased lopinavir AUCoral in all CYP3A-containing mouse strains.Conclusions and implications:
CYP3A was the major determinant of lopinavir pharmacokinetics, far more than Abcb1a/b. Both intestinal and hepatic CYP3A activity contributed importantly to low oral bioavailability of lopinavir. Ritonavir increased lopinavir bioavailability primarily by inhibiting CYP3A. Effects of Abcb1a/b were only detectable in the presence of CYP3A, suggesting saturation of Abcb1a/b in the absence of CYP3A activity. 相似文献AIMS
The pharmacokinetics (PK) and pharmacogenetics (PG) of nevirapine have been studied in rich and limited-resource countries. CYP2B6 single nucleotide polymorphisms (SNPs) have been associated with decreased drug clearance. We evaluated the PG determinants of nevirapine trough concentrations in a rural cohort in Burundi using easy to store and transport dried sample spot devices.METHODS
A cross-sectional analysis in HIV-positive nevirapine-treated patients in Kiremba, north of Burundi, was performed in 2009. After blood withdrawal whole blood was stored on dried blood spots and plasma (after centrifugation) was placed on dried plasma spot devices and stored at room temperature. Nevirapine plasma and dried sample spot concentrations were compared to test the clinical usefulness of this method. SNPs in CYP2B6 and ABCB1 (using a real time PCR technique) were analyzed and associated with nevirapine plasma trough concentrations.RESULTS
Nevirapine concentrations measured on dried plasma spot devices were highly related to plasma concentrations in 60 patients, although a negative bias was observed (−18%). Nevirapine trough concentrations were above the target concentration (3000 ng ml−1) in 84% of patients and they were associated with CYP2B6 SNPs (both at position 516 and 983). No effect of ABCB1 SNPs was noted.CONCLUSIONS
Dried plasma spot devices are accurate tools for measuring nevirapine concentrations in rural settings where refrigeration is not available, despite a moderate underestimation bias. They allowed the evaluation of nevirapine concentrations in a cohort of HIV-infected people in rural Burundi, confirming very good exposure and correlation with PG polymorphisms in the CYP2B6 encoding gene. 相似文献This study was to investigate the effect of concomitantly administered curcumin on the pharmacokinetics of talinolol and association with ABCB1 C3435T genetic polymorphism.
A two-phase, randomized, single-blind, crossover study was carried out in 18 healthy male volunteers with different genotypes of ABCB1, including C3435C (CC, n = 6), C3435T (CT, n = 6) and T3435T (TT, n = 6). The pharmacokinetics of talinolol were measured after co-administration of placebo or 1000?mg curcumin capsules once daily for 14 days.
The AUC0–48 h and AUC0–∞ of talinolol were increased by 67.0% (95% CI: 1.09~2.25; p = 0.002) and 80.8% (95% CI: 0.92~2.69; p = 0.005) respectively with curcumin co-administration. The Cmax of talinolol was significantly higher after curcumin administration as compared with placebo (p = 0.029).The CL/F of talinolol was decreased by 25.9% (p = 0.005) during the curcumin-treated phase. No significant change in tmax and t1/2 of talinolol were observed between the placebo- and curcumin-treated phases. AUC0–48, AUC0–∞, Cmax of talinolol were extensively increased and CLoral/F decreased in TT subjects.
Co-administration of curcumin significantly increased the plasma concentration of talinolol in healthy volunteers. The effect of curcumin on talinolol was associated with ABCB1 genotypes (C3435T).
Aim:
Cyclosporine requires close therapeutic drug monitoring because of its narrow therapeutic index and marked inter-individual pharmacokinetic variation. In this study, we investigated the associations of CYP3A4, CYP3A5, ABCB1, NFKB1, and NR1I2 polymorphisms with cyclosporine concentrations in Chinese renal transplant recipients in the early period after renal transplantation.Methods:
A total of 101 renal transplant recipients receiving cyclosporine were genotyped for CYP3A4*1G, CYP3A5*3, ABCB1 C1236T, G2677T/A, C3435T, NFKB1 −94 ins/del ATTG, and NR1I2 polymorphisms. Cyclosporine whole blood levels were measured by a fluorescence polarization immunoassay. Trough concentrations of cyclosporine were determined for days 7-18 following transplantation.Results:
The dose-adjusted trough concentration (C0) of cyclosporine in ABCB1 2677 TT carriers was significantly higher than that in GG carriers together with GT carriers [90.4±24.5 vs 67.8±26.8 (ng/mL)/(mg/kg), P=0.001]. ABCB1 3435 TT carriers had a significantly higher dose-adjusted C0 of cyclosporine than CC carriers together with CT carriers [92.0±24.0 vs 68.4±26.5 (ng/mL)/(mg/kg), P=0.002]. Carriers of the ABCB1 1236TT-2677TT-3435TT haplotype had a considerably higher CsA C0/D than carriers of other genotypes [97.2±21.8 vs 68.7±26.9 (ng/mL)/(mg/kg), P=0.001]. Among non-carriers of the ABCB1 2677 TT and 3435 TT genotypes, patients with the NFKB1 −94 ATTG ins/ins genotype had a significantly higher dose-adjusted C0 than those with the −94 ATTG del/del genotype [75.9±32.9 vs 55.1±15.1 (ng/mL)/(mg/kg), P=0.026].Conclusion:
These results illustrate that the ABCB1 and NFKB1 genotypes are closely correlated with cyclosporine trough concentrations, suggesting that these SNPs are useful for determining the appropriate dose of cyclosporine. 相似文献Aims
Tacrolimus (TAC) is one of the most successful immunosuppressive drugs in transplantation. Its pharmacokinetics (PK) and pharmacogenetics (PG) have been extensively studied, with many studies showing the influence of CYP3A5 on TAC metabolism and bioavailability. However, data concerning the functional significance of ABCB1 polymorphisms are uncertain due to inconsistent results. We evaluated the association between ABCB1 diplotypes, CYP3A5 polymorphisms and TAC disposition in a cohort of Brazilian transplant recipients.Methods
Individuals were genotyped for the CYP3A5*3 allele and ABCB1 polymorphisms (2677G>A/T, 1236C>T, 3435C/T) using a TaqMan® PCR technique. Diplotypes were analyzed for correlation with the TAC dose-normalized ratio (Co : dose).Results
We genotyped 108 Brazilian kidney recipients for CYP3A5 (11% CYP3A5*1/*1; 31% CYP3A5*1/*3 and 58% CYP3A5*3/*3) and ABCB1 haplotypes (42% CGC/CGC; 41% GCG/TTT and 17% TTT/TTT). Homozygous subjects for the CYP3A5*3 allele or carriers of the ABCB1 TTT/TTT diplotype showed a higher Co : dose ratio compared with wild type subjects [median (interquartile range) 130.2 (97.5–175.4) vs. 71.3 (45.6–109.0), P < 0.0001 and 151.8 (112.1–205.6) vs. 109.6 (58.1–132.9), P = 0.01, respectively]. When stratified for the CYP3A5*3 group, ABCB1 TTT/TTT individuals showed a higher Co : dose ratio compared with non-TTT/TTT individuals [167.8 (130.4–218.0) vs. 119.4 (100.2–166.3), P = 0.04]. Multivariate linear regression analysis showed that the effects of CYP3A5 polymorphisms and ABCB1 diplotypes remained significant after correction for confounding factors.Conclusions
CYP3A5 is the major enzyme responsible for the marked interindividual variability in TAC PK, but it cannot be considered alone when predicting dose adjustment because ABCB1 diplotypes also affect TAC disposition, showing independent and additive effects on the TAC dose-normalized concentration. 相似文献Objectives
The objectives of this study were to determine if ABCB1 polymorphisms are associated with interindividual variability in sitagliptin pharmacokinetics and if atorvastatin alters the pharmacokinetic disposition of sitagliptin in healthy volunteers.Methods
In this open-label, randomized, two-phase crossover study, healthy volunteers were prospectively stratified according to ABCB1 1236/2677/3435 diplotype (n?=?9, CGC/CGC; n?=?10, CGC/TTT; n?=?10, TTT/TTT). In one phase, participants received a single 100 mg dose of sitagliptin; in the other phase, participants received 40 mg of atorvastatin for 5 days, with a single 100 mg dose of sitagliptin administered on day 5. A 24-h pharmacokinetic study followed each sitagliptin dose, and the study phases were separated by a 14-day washout period.Results
Sitagliptin pharmacokinetic parameters did not differ significantly between ABCB1 CGC/CGC, CGC/TTT, and TTT/TTT diplotype groups during the monotherapy phase. Atorvastatin administration did not significantly affect sitagliptin pharmacokinetics, with geometric mean ratios (90 % confidence intervals) for sitagliptin maximum plasma concentration, plasma concentration–time curve from zero to infinity, renal clearance, and fraction of sitagliptin excreted unchanged in the urine of 0.93 (0.86–1.01), 0.96 (0.91–1.01), 1.02 (0.93–1.12), and 0.98 (0.90–1.06), respectively.Conclusions
ABCB1 CGC/CGC, CGC/TTT, and TTT/TTT diplotypes did not influence sitagliptin pharmacokinetics in healthy volunteers. Furthermore, atorvastatin had no effect on the pharmacokinetics of sitagliptin in the setting of ABCB1 CGC/CGC, CGC/TTT, and TTT/TTT diplotypes. 相似文献To evaluate the effects of dietary salt on the stereoselective disposition of verapamil enantiomers in relation to the transporter ABCB1 2677GG/3435CC and 2677TT/3435TT haplotypes, ten healthy subjects were asked to take diets of three different salt levels for 7 days in a randomized, three-way crossover manner.
The plasma concentrations of verapamil and norverapamil enantiomers were determined after a single oral dose of 240 mg verapamil on the last day of each phase. Pharmacokinetic parameters were calculated by non-compartmental analysis techniques and compared among the three different dietary salt phases.
Compared with the medium salt diet, the high and low salt diets had no significant effect on the disposition of verapamil enantiomers. Moreover, the ABCB1 haplotypes did not alter the impact of dietary salt, although ABCB1 2677TT/3435TT subjects had slightly, but not significantly, higher Cmax and area under the curve (AUC) and lower Tmax for the verapamil enantiomers than did 2677GG/3435CC subjects in each salt phase.