Aleksi Tornio

Trimethoprim and the CYP2C8*3 allele have opposite effects on the pharmacokinetics of pioglitazone.

We studied the effects of the CYP2C8 inhibitor trimethoprim and CYP2C8 genotype on the pharmacokinetics of the antidiabetic pioglitazone. In a randomized crossover study, 16 healthy volunteers with the CYP2C8*1/*1 (n = 8), *1/*3 (n = 5), or *3/*3 (n = 3) genotype ingested 160 mg of trimethoprim or placebo twice daily for 6 days. On day 3, they ingested 15 mg of pioglitazone. The effects of trimethoprim on pioglitazone were characterized in vitro. Trimethoprim raised the area under the plasma pioglitazone concentration-time curve (AUC0–∞) by 42% (p < 0.001) and decreased the formation rates of pioglitazone metabolites M-IV and M-III (p < 0.001). During the placebo phase, the weight-adjusted AUC0–∞ of pioglitazone was 34% smaller in the CYP2C8*3/*3 group and 26% smaller in the CYP2C8*1/*3 group than in the CYP2C8*1/*1 group (p < 0.05). Trimethoprim inhibited M-IV formation in vitro (inhibition constant 38.2 μM), predicting the in vivo interaction. In conclusion, drug interactions and pharmacogenetics affecting the CYP2C8 enzyme may change the safety of pioglitazone.

The Effect of Gemfibrozil on Repaglinide Pharmacokinetics Persists for at Least 12 h After the Dose: Evidence for Mechanism‐based Inhibition of CYP2C8 In Vivo

Repaglinide is metabolized by cytochrome P450 (CYP) 2C8 and 3A4. Gemfibrozil has the effect of increasing the area under the concentration–time curve (AUC) of repaglinide eightfold. We studied the effect of dosing interval on the extent of the gemfibrozil–repaglinide interaction. In a randomized five‐phase crossover study, 10 healthy volunteers ingested 0.25 mg repaglinide, with or without gemfibrozil pretreatment. Plasma repaglinide, gemfibrozil, their metabolites, and blood glucose were measured. When the last dose of 600 mg gemfibrozil was ingested simultaneously with repaglinide, or 3, 6, or 12 h before, it increased the AUC0–∞ of repaglinide 7.0‐, 6.5‐, 6.2‐ and 5.0‐fold, respectively (P < 0.001). The peak repaglinide concentration increased approximately twofold (P < 0.001), and the half‐life was prolonged from 1.2 h to 2–3 h (P < 0.001) during all the gemfibrozil phases. The drug interaction effects persisted at least 12 h after gemfibrozil was administered, although plasma gemfibrozil and gemfibrozil 1‐O‐β‐glucuronide concentrations were only 5 and 10% of their peak values, respectively. The long‐lasting interaction is likely caused by mechanism‐based inhibition of CYP2C8 by gemfibrozil glucuronide.

Glucuronidation Converts Clopidogrel to a Strong Time‐Dependent Inhibitor of CYP2C8: A Phase II Metabolite as a Perpetrator of Drug–Drug Interactions

Cerivastatin and repaglinide are substrates of cytochrome P450 (CYP)2C8, CYP3A4, and organic anion–transporting polypeptide (OATP)1B1. A recent study revealed an increased risk of rhabdomyolysis in patients using cerivastatin with clopidogrel, warranting further studies on clopidogrel interactions. In healthy volunteers, repaglinide area under the concentration–time curve (AUC0–∞) was increased 5.1–fold by a 300–mg loading dose of clopidogrel and 3.9–fold by continued administration of 75 mg clopidogrel daily. In vitro, we identified clopidogrel acyl–β–D–glucuronide as a potent time–dependent inhibitor of CYP2C8. A physiologically based pharmacokinetic model indicated that inactivation of CYP2C8 by clopidogrel acyl–β–D–glucuronide leads to uninterrupted 60–85% inhibition of CYP2C8 during daily clopidogrel treatment. Computational modeling resulted in docking of clopidogrel acyl–β–D–glucuronide at the CYP2C8 active site with its thiophene moiety close to heme. The results indicate that clopidogrel is a strong CYP2C8 inhibitor via its acyl–β–D–glucuronide and imply that glucuronide metabolites should be considered potential inhibitors of CYP enzymes.

Drug interactions with oral antidiabetic agents: pharmacokinetic mechanisms and clinical implications

There is a growing epidemic of type 2 diabetes (T2DM), and it is associated with various comorbidities. Patients with T2DM are usually treated with multiple drugs, and are therefore at an increased risk of harmful drug-drug interactions (DDIs). Several potentially life-threatening DDIs concerning oral antidiabetic drugs have been identified. This has mostly been initiated by case reports but, more recently, the understanding of their mechanisms has greatly increased. In this article, we review the pharmacokinetic DDIs concerning oral antidiabetics, including metformin, sulfonylureas, meglitinide analogs, thiazolidinediones and dipeptidyl peptidase-4 inhibitors, and the underlying mechanistic basis that can help to predict and prevent DDIs. In particular, the roles of membrane transporters and cytochrome P450 (CYP) enzymes in these DDIs are discussed.

CYP2C8 Activity Recovers within 96 Hours after Gemfibrozil Dosing: Estimation of CYP2C8 Half-Life Using Repaglinide as an in Vivo Probe

Gemfibrozil 1-O-β-glucuronide is a mechanism-based inhibitor of cytochrome P450 2C8. We studied the recovery of CYP2C8 activity after discontinuation of gemfibrozil treatment using repaglinide as a probe drug, to estimate the in vivo turnover half-life of CYP2C8. In a randomized five-phase crossover study, nine healthy volunteers ingested 0.25 mg of repaglinide alone or after different time intervals after a 3-day treatment with 600 mg of gemfibrozil twice daily. The area under the plasma concentration-time curve (AUC) from time 0 to infinity of repaglinide was 7.6-, 2.9-, 1.4- and 1.0-fold compared with the control phase when it was administered 1, 24, 48, or 96 h after the last gemfibrozil dose, respectively (P < 0.001 versus control for 1, 24, and 48 h after gemfibrozil). Thus, a strong CYP2C8 inhibitory effect persisted even after gemfibrozil and gemfibrozil 1-O-β-glucuronide concentrations had decreased to less than 1% of their maximum (24-h dosing interval). In addition, the metabolite to repaglinide AUC ratios indicated that significant (P < 0.05) inhibition of repaglinide metabolism continued up to 48 h after gemfibrozil administration. Based on the recovery of repaglinide oral clearance, the in vivo turnover half-life of CYP2C8 was estimated to average 22 ± 6 h (mean ± S.D.). In summary, CYP2C8 activity is recovered gradually during days 1 to 4 after gemfibrozil discontinuation, which should be considered when CYP2C8 substrate dosing is planned. The estimated CYP2C8 half-life will be useful for in vitro-in vivo extrapolations of drug-drug interactions involving induction or mechanism-based inhibition of CYP2C8.

Carboxylesterase 1 c.428G>A single nucleotide variation increases the antiplatelet effects of clopidogrel by reducing its hydrolysis in humans

Carboxylesterase 1 (CES1) hydrolyzes the prodrug clopidogrel to an inactive carboxylic acid metabolite. We studied the pharmacokinetics and pharmacodynamics of 600 mg oral clopidogrel in healthy white volunteers, including 10 carriers and 12 noncarriers of CES1 c.428G>A (p.Gly143Glu, rs71647871) single nucleotide variation (SNV). Clopidogrel carboxylic acid to clopidogrel area under the plasma concentration‐time curve from 0 hours to infinity (AUC0–∞) ratio was 53% less in CES1 c.428G>A carriers than in noncarriers (P = 0.009), indicating impaired hydrolysis of clopidogrel. Consequently, the AUC0–∞ of clopidogrel and its active metabolite were 123% (P = 0.004) and 67% (P = 0.009) larger in the c.428G>A carriers than in noncarriers. Consistent with these findings, the average inhibition of P2Y12‐mediated platelet aggregation 0–12 hours after clopidogrel intake was 19 percentage points higher in the c.428G>A carriers than in noncarriers (P = 0.036). In conclusion, the CES1 c.428G>A SNV increases clopidogrel active metabolite concentrations and antiplatelet effects by reducing clopidogrel hydrolysis to inactive metabolites.

Grapefruit Juice Inhibits the Metabolic Activation of Clopidogrel

Cytochrome P450 (CYP) enzymes, including CYP2C19 and CYP3A4, participate in the bioactivation of clopidogrel. Grapefruit juice constituents potently inactivate intestinal CYP3A4 and have been shown to inhibit CYP2C19 as well. In a randomized crossover study, 14 healthy volunteers ingested 200 ml of grapefruit juice or water three times daily for 3 days. On day 3, they ingested a single 600‐mg dose of clopidogrel. Grapefruit juice reduced the peak plasma concentration (Cmax) of the active metabolite of clopidogrel to 13% of the control (range 11–17%, P < 0.001) and the area under the plasma concentration–time curve from 0 to 3 h to 14% (range 12–17%, P < 0.001) of the control, but it had no significant effect on the parent clopidogrel. Moreover, grapefruit juice markedly decreased the platelet‐inhibitory effect of clopidogrel, as assessed with the VerifyNow P2Y12 test in two of the participants. In conclusion, concomitant use of grapefruit juice may impair the efficacy of clopidogrel. Therefore, the use of grapefruit juice is best avoided during clopidogrel therapy.

Grapefruit juice markedly increases the plasma concentrations and antiplatelet effects of ticagrelor in healthy subjects

AIM This study examined the effects of grapefruit juice on the new P2Y12 inhibitor ticagrelor, which is a substrate of CYP3A4 and P-glycoprotein. METHODS In a randomized crossover study, 10 healthy volunteers ingested 200 ml of grapefruit juice or water thrice daily for 4 days. On day 3, they ingested a single 90 mg dose of ticagrelor. RESULTS Grapefruit juice increased ticagrelor geometric mean peak plasma concentration (Cmax ) to 165% (95% confidence interval 147, 184%) and area under the concentration-time curve (AUC(0,∞)) to 221% of control (95% confidence interval 200, 245%). The Cmax and AUC(0,34 h) (P < 0.05) but not the AUC(0,∞) of the active metabolite C12490XX were decreased significantly. Grapefruit juice had a minor effect on ticagrelor elimination half-life prolonging it from 6.7 to 7.2 h (P = 0.036). In good correlation with the elevated plasma ticagrelor concentrations, grapefruit juice enhanced the antiplatelet effect of ticagrelor, assessed with VerifyNow® and Multiplate® methods, and postponed the recovery of platelet reactivity. CONCLUSIONS Grapefruit juice increased ticagrelor exposure by more than two-fold, leading to an enhanced and prolonged ticagrelor antiplatelet effect. The grapefruit juice-ticagrelor interaction seems clinically important and indicates the significance of intestinal metabolism to ticagrelor pharmacokinetics.

Effect of carboxylesterase 1 c.428G > A single nucleotide variation on the pharmacokinetics of quinapril and enalapril

AIM The aim of the present study was to investigate the effects of the carboxylesterase 1 (CES1) c.428G > A (p.G143E, rs71647871) single nucleotide variation (SNV) on the pharmacokinetics of quinapril and enalapril in a prospective genotype panel study in healthy volunteers. METHODS In a fixed-order crossover study, 10 healthy volunteers with the CES1 c.428G/A genotype and 12 with the c.428G/G genotype ingested a single 10 mg dose of quinapril and enalapril with a washout period of at least 1 week. Plasma concentrations of quinapril and quinaprilat were measured for up to 24 h and those of enalapril and enalaprilat for up to 48 h. Their excretion into the urine was measured from 0 h to 12 h. RESULTS The area under the plasma concentration-time curve from 0 h to infinity (AUC0-∞) of active enalaprilat was 20% lower in subjects with the CES1 c.428G/A genotype than in those with the c.428G/G genotype (95% confidence interval of geometric mean ratio 0.64, 1.00; P = 0.049). The amount of enalaprilat excreted into the urine was 35% smaller in subjects with the CES1 c.428G/A genotype than in those with the c.428G/G genotype (P = 0.044). The CES1 genotype had no significant effect on the enalaprilat to enalapril AUC0-∞ ratio or on any other pharmacokinetic or pharmacodynamic parameters of enalapril or enalaprilat. The CES1 genotype had no significant effect on the pharmacokinetic or pharmacodynamic parameters of quinapril. CONCLUSIONS The CES1 c.428G > A SNV decreased enalaprilat concentrations, probably by reducing the hydrolysis of enalapril, but had no observable effect on the pharmacokinetics of quinapril.

Gemfibrozil Impairs Imatinib Absorption and Inhibits the CYP2C8‐Mediated Formation of Its Main Metabolite

Cytochrome P450 (CYP) 3A4 is considered the most important enzyme in imatinib biotransformation. In a randomized, crossover study, 10 healthy subjects were administered gemfibrozil 600 mg or placebo twice daily for 6 days, and imatinib 200 mg on day 3, to study the significance of CYP2C8 in imatinib pharmacokinetics. Unexpectedly, gemfibrozil reduced the peak plasma concentration (Cmax) of imatinib by 35% (P < 0.001). Gemfibrozil also reduced the Cmax and area under the plasma concentration–time curve (AUC0–∞) of N‐desmethylimatinib by 56 and 48% (P < 0.001), respectively, whereas the AUC0–∞ of imatinib was unaffected. Furthermore, gemfibrozil reduced the Cmax/plasma concentration at 24 h (C24 h) ratios of imatinib and N‐desmethylimatinib by 44 and 17% (P < 0.05), suggesting diminished daily fluctuation of imatinib plasma concentrations during concomitant use with gemfibrozil. Our findings indicate significant participation of CYP2C8 in the metabolism of imatinib in humans, and support involvement of an intestinal influx transporter in imatinib absorption.