Genetic polymorphism in SLCO1B1 is a major determinant of interindividual variability in the pharmacokinetics of repaglinide. The effect of SLCO1B1 polymorphism on the pharmacokinetics of repaglinide may be clinically important.

Cyclosporine raised the plasma concentrations of repaglinide, probably by inhibiting its CYP3A4-catalyzed biotransformation and OATP1B1-mediated hepatic uptake. Coadministration of cyclosporine may enhance the blood glucose-lowering effect of repaglinide and increase the risk of hypoglycemia.

Abstract:Repaglinide is an antidiabetic drug metabolised by cytochrome P450 (CYP) 2C8 and CYP3A4 enzymes. To clarify the mechanisms of observed repaglinide drug interactions, we determined the contribution of the two enzymes to repaglinide metabolism at different substrate concentrations, and examined the effect of fibrates and rifampicin on CYP2C8, CYP3A4 and repaglinide metabolism in vitro. We studied repaglinide metabolism using pooled human liver microsomes, recombinant CYP2C8 and recombinant CYP3A4 enzymes. The effect of quercetin and itraconazole on repaglinide metabolism, and of gemfibrozil, bezafibrate, fenofibrate and rifampicin on CYP2C8 (paclitaxel 6a-hydroxylation) and CYP3A4 (midazolam 1-hydroxylation) activities and repaglinide metabolism were studied using human liver microsomes. At therapeutic repaglinide concentrations (Ͻ0.4 mM), CYP2C8 and CYP3A4 metabolised repaglinide at similar rates. Quercetin (25 mM) and itraconazole (3 mM) inhibited the metabolism of 0.2 mM repaglinide by 58% and 71%, and that of 2 mM repaglinide by 56% and 59%, respectively. The three fibrates inhibited CYP2C8 (K i : bezafibrate 9.7 mM, gemfibrozil 30.4 mM and fenofibrate 92.6 mM) and repaglinide metabolism (IC 50 : bezafibrate 37.7 mM, gemfibrozil 111 mM and fenofibrate 164 mM), but had no effect on CYP3A4. Rifampicin inhibited CYP2C8 (K i 30.2 mM), CYP3A4 (K i 18.5 mM) and repaglinide metabolism (IC 50 13.7 mM). In conclusion, both CYP2C8 and CYP3A4 are important in the metabolism of therapeutic concentrations of repaglinide in vitro, but their predicted contributions in vivo are highly dependent on the scaling factor used. Gemfibrozil is only a moderate inhibitor of CYP2C8 and does not inhibit CYP3A4; inhibition of CYP-enzymes by parent gemfibrozil alone does not explain its interaction with repaglinide in vivo. Rifampicin competitively inhibits both CYP2C8 and CYP3A4, which can counteract its inducing effect in humans.Repaglinide is a short-acting antidiabetic drug, used in type 2 diabetic patients to normalise postprandial hyperglycaemia (Gromada et al. 1995;Hatorp 2002). Repaglinide is eliminated by metabolism to at least 5 different metabolites, as shown in vivo (van Heiningen et al. 1999) and in vitro (Bidstrup et al. 2003). CYP2C8 and CYP3A4 are the principal enzymes in its oxidative biotransformation, when studied at high (about 100-fold therapeutic) repaglinide concentrations (Bidstrup et al. 2003). However, the contribution of CYP2C8 and CYP3A4 to the metabolism of clinically relevant concentrations of repaglinide in vitro is not known and needs to be clarified in order to solve the interaction potential of repaglinide.The plasma concentrations of repaglinide are increased by several drugs which inhibit either CYP3A4 or CYP2C8 enzymes (Niemi et al. 2001(Niemi et al. , 2003a(Niemi et al. & 2004. Itraconazole and clarithromycin (selective inhibitors of CYP3A4) have increased the mean area under the plasma concentrationtime curve (AUC) of repaglinide by about 40%, whereas trimethoprim (selective inhibitor of CYP...

The effects of five HIV protease inhibitors (amprenavir, indinavir, nelfinavir, ritonavir and saquinavir) on cytochrome P450 (CYP) 3A4, 3A5 and 3A7 activities were studied in vitro using testosterone 6b-hydroxylation in recombinant CYP3A4, CYP3A5 and CYP3A7 enzymes. The protease inhibitors showed differential inhibitory effects on the three CYP3A forms. Ritonavir and saquinavir were non-selective and preferential inhibitors of CYP3A4 and CYP3A5 (K i 0.03 mM and 0.6-0.8 mM for ritonavir and saquinavir, respectively), and weaker inhibitors of CYP3A7 (K i 0.6 mM and 1.8 mM, respectively). Nelfinavir was a potent and non-selective inhibitor of all three CYP3A forms (K i 0.3-0.4 mM). Amprenavir and indinavir preferentially inhibited CYP3A4 (K i 0.1 mM and 0.2 mM, respectively), with weaker inhibitory effects on CYP3A5 (K i 0.5 mM and 2.2 mM, respectively) and CYP3A7 (K i 2.1 mM and 10.6 mM, respectively). In conclusion, significant differences exist in the inhibitory potency of protease inhibitors for different CYP3A forms. Ritonavir, nelfinavir, saquinavir and amprenavir seem to be prone to drug-drug interactions by inhibiting both CYP3A4 and CYP3A5. Especially nelfinavir and ritonavir also have a potential to inhibit foetal CYP3A7-mediated drug metabolism and some endogenous pathways that may be crucial to normal foetal development, while indinavir has the lowest potential to inhibit CYP3A5 and CYP3A7.

AimsOur aim was to investigate the effect of the CYP2C8 inhibitor trimethoprim on the pharmacokinetics and pharmacodynamics of the antidiabetic drug repaglinide, and to examine the influence of the former on the metabolism of the latter in vitro . MethodsIn a randomized, double-blind, crossover study with two phases, nine healthy volunteers took 160 mg trimethoprim or placebo orally twice daily for 3 days. On day 3, 1 h after the last dose of trimethoprim or placebo, they ingested a single 0.25 mg dose of repaglinide. Plasma repaglinide and blood glucose concentrations were measured for up to 7 h post-dose. In addition, the effect of trimethoprim on the metabolism of repaglinide by human liver microsomes was investigated. ResultsTrimethoprim raised the AUC(0, • ) and C max of repaglinide by 61% (range, 30-117%; P = 0.0008) and 41% ( P = 0.005), respectively, and prolonged the t 1 / 2 of repaglinide from 0.9 to 1.1 h ( P = 0.001). Trimethoprim had no significant effect on the pharmacokinetics of its aromatic amine metabolite (M1), but decreased the M1 : repaglinide AUC(0, • ) ratio by 38% ( P = 0.0005). No effect of trimethoprim on the blood glucose-lowering effect of repaglinide was detectable. In vitro , trimethoprim inhibited the metabolism of (220 n M ) repaglinide in a concentration-dependent manner. ConclusionsTrimethoprim raised the plasma concentrations of repaglinide probably by inhibiting its CYP2C8-mediated biotransformation. Although the interaction did not significantly enhance the effect of repaglinide on blood glucose concentration at the drug doses used, the possibility of an increased risk of hypoglycaemia should be considered during concomitant use of trimethoprim and repaglinide in patients with diabetes.

Cytochrome P450 2C8 (CYP2C8) plays a major role in the metabolism of therapeutically important drugs which exhibit large interindividual differences in their pharmacokinetics. In order to evaluate any genetic influence on this variation, a CYP2C8 phenotype-genotype evaluation was carried out in Caucasians. Two novel CYP2C8 haplotypes, named B and C with frequencies of 24 and 22% in Caucasians, respectively, were identified and caused a significantly increased and reduced paclitaxel 6alpha-hydroxylation, respectively, as evident from analyses of 49 human liver samples. In healthy white subjects, CYP2C8*3 and the two novel haplotypes significantly influenced repaglinide pharmacokinetics in SLCO1B1c.521T/C heterozygous individuals: haplotype B was associated with reduced and haplotype C with increased repaglinide AUC (0-infinity). Functional studies suggested -271C>A (CYP2C8*1B) as a causative SNP in haplotype B. In conclusion, two novel common CYP2C8 haplotypes were identified and significantly associated with altered rate of CYP2C8-dependent drug metabolism in vitro and in vivo.

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Telithromycin, but not montelukast, increases the plasma concentrations and effects of the cytochrome P450 3A4 and 2C8 substrate repaglinide Background and Objective: The antidiabetic repaglinide is metabolized by cytochrome P450 (CYP) 2C8 and CYP3A4. Telithromycin, an antimicrobial agent, inhibits CYP3A4 in vitro and in vivo. Montelukast, an antiasthmatic drug, is a potent inhibitor of CYP2C8 in vitro. We studied the effects of telithromycin, montelukast, and the combination of telithromycin and montelukast on the pharmacokinetics and pharmacodynamics of repaglinide. Methods: In a randomized 4-phase crossover study, 12 healthy volunteers received 800 mg telithromycin, 10 mg montelukast, both telithromycin and montelukast, or placebo once daily for 3 days. On day 3, they ingested a single 0.25-mg dose of repaglinide. Plasma and urine concentrations of repaglinide and its metabolites M1, M2, and M4, as well as blood glucose concentrations, were measured for 12 hours. Results: Telithromycin alone raised the mean peak plasma repaglinide concentration to 138% (range, 91%-209%; P ‫؍‬ .006) and the total area under the plasma concentration-time curve from 0 hours to infinity [AUC(0-ؕ)] of repaglinide to 177% (range, 125%-257%; P < .001) of control (placebo). Telithromycin reduced the AUC(0-ؕ) ratio of the metabolite M1 to repaglinide by 68% (P < .001) and the urinary excretion ratio of M1 to repaglinide by 77% (P ‫؍‬ .001). In contrast to previous estimates based on in vitro CYP2C8 inhibition data, montelukast had no significant effect on the pharmacokinetics of repaglinide or its metabolites and did not significantly alter the effect of telithromycin on repaglinide pharmacokinetics. Telithromycin, unlike montelukast, lowered the maximum blood glucose concentration (P ‫؍‬ .002) and mean blood glucose concentration from 0 to 3 hours (P ‫؍‬ .008) after repaglinide intake, as compared with placebo. Conclusions: Telithromycin increases the plasma concentrations and blood glucose-lowering effect of repaglinide by inhibiting its CYP3A4-catalyzed biotransformation and may increase the risk of hypoglycemia. Unexpectedly, montelukast has no significant effect on repaglinide pharmacokinetics, suggesting that it does not significantly inhibit CYP2C8 in vivo. The low free fraction of montelukast in plasma may explain the lack of effect on CYP2C8 in vivo, despite the low in vitro inhibition constant, highlighting the importance of incorporating plasma protein binding to interaction predictions. (Clin Pharmacol Ther 2006;79:231-42.)