Effects of gemfibrozil, itraconazole, and their combination on the pharmacokinetics of pioglitazone.
ABSTRACT The thiazolidinedione antidiabetic drug pioglitazone is metabolized mainly by cytochrome P450 (CYP) 2C8 and CYP3A4 in vitro. Our objective was to study the effects of gemfibrozil, itraconazole, and their combination on the pharmacokinetics of pioglitazone to determine the role of these enzymes in the fate of pioglitazone in humans.
In a randomized, double-blind, 4-phase crossover study, 12 healthy volunteers took either 600 mg gemfibrozil or 100 mg itraconazole (first dose, 200 mg), both gemfibrozil and itraconazole, or placebo twice daily for 4 days. On day 3, they received a single dose of 15 mg pioglitazone. Plasma drug concentrations and the cumulative excretion of pioglitazone and its metabolites into urine were measured for up to 48 hours.
Gemfibrozil alone raised the mean total area under the plasma concentration-time curve from time 0 to infinity [AUC(0-infinity)] of pioglitazone 3.2-fold (range, 2.3-fold to 6.5-fold; P < .001) and prolonged its elimination half-life (t (1/2) ) from 8.3 to 22.7 hours ( P < .001) but had no significant effect on its peak concentration (C max ) compared with placebo (control). Gemfibrozil increased the 48-hour excretion of pioglitazone into urine by 2.5-fold ( P < .001) and reduced the ratios of the active metabolites M-III and M-IV to pioglitazone in plasma and urine. Gemfibrozil decreased the area under the plasma concentration-time curve from time 0 to 48 hours [AUC(0-48)] of the metabolites M-III and M-IV by 42% ( P < .05) and 45% ( P < .001), respectively, but their total AUC(0-infinity) values were reduced by less or not at all. Itraconazole had no significant effect on the pharmacokinetics of pioglitazone and did not alter the effect of gemfibrozil on pioglitazone pharmacokinetics. The mean area under the concentration versus time curve to 49 hours [AUC(0-49)] of itraconazole was 46% lower ( P < .001) during the gemfibrozil-itraconazole phase than during the itraconazole phase.
Gemfibrozil elevates the plasma concentrations of pioglitazone, probably by inhibition of its CYP2C8-mediated metabolism. CYP2C8 appears to be of major importance and CYP3A4 of minor importance in pioglitazone metabolism in vivo in humans. Concomitant use of gemfibrozil with pioglitazone may increase the effects and risk of dose-related adverse effects of pioglitazone. However, studies in diabetic patients are needed to determine the clinical significance of the gemfibrozil-pioglitazone interaction.
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ABSTRACT: The incidence of type 2 diabetes mellitus is increasing rapidly, as are the associated co-morbidities. Consequently, it has become necessary for a diabetic patient to take multiple medications at the same time to delay progression of the disease. This can put patients at an increased risk of moderate to severe drug interactions, which may threaten patients' life or may deteriorate the quality of their life. Hence, managing drug-drug interactions is the cornerstone of anti-diabetic therapy. Most of the clinically important drug-drug interactions of anti-diabetic agents are related to their metabolic pathways, but drugs that compete for renal excretion or impair renal status can also play an important role. In this review, we have examined the clinical implications and underlying mechanisms of drugs that are likely to alter the pharmacologic response of or cause adverse events with antidiabetic drugs, and we have outlined safe and efficacious treatment modalities.Drug Safety 09/2014; · 2.62 Impact Factor
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ABSTRACT: Anemia, a frequent complication of chronic kidney disease, is most commonly treated with recombinant human erythropoiesis-stimulating agents. Oral administration of GSK1278863, a prolyl hydroxylase inhibitor, results in the accumulation of hypoxia-inducible factor 1α, and stimulates erythropoiesis by triggering the pathways involved in innate hypoxia. In vitro biotransformation data indicate that GSK1278863 is primarily metabolized by CYP2C8. This study assessed the pharmacokinetics of single-dose (100 mg) GSK1278863 administered alone, or co-administered with a high-fat/high-calorie meal or steady-state gemfibrozil (a strong CYP2C8 and OATP1B1 inhibitor). Co-administration of single-dose 100 mg GSK1278863 with a high-fat/high-calorie meal did not significantly affect the plasma exposure of GSK1278863 or its 6 predominant metabolites. Co-administration of GSK1278863 with steady-state gemfibrozil resulted in an 18.6-fold increase in the area under the curve from time 0 to infinity (AUC(0–∞)) of GSK1278863. Additionally, the maximum plasma concentration (Cmax) and terminal elimination half-life increased 3.92- and 3.70-fold, respectively. The appearance of metabolites was delayed, and their Cmax and AUC(0–∞) were reduced by at least 90% and 62%, respectively. These findings indicate that GSK1278863 can be safely administered without regard to food. Until further studies with weaker CYP2C8 inhibitors are conducted, co-administration of GSK1278863 with CYP2C8 inhibitors should be avoided.Clinical Pharmacology in Drug Development. 10/2013; 3(2).
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ABSTRACT: Previous studies have shown that several protein kinase inhibitors are time-dependent inhibitors of cytochrome P450 3A (CYP3A). We screened fourteen kinase inhibitors for time-dependent inhibition of CYP2C8 and CYP3A. Amodiaquine N-deethylation and midazolam 1'-hydroxylation were used as marker reactions for CYP2C8 and CYP3A activity, respectively. A screening, IC50-shift, and mechanism-based inhibition were assessed with human liver microsomes. In the screening, bosutinib isomer 1, crizotinib, dasatinib, erlotinib, gefitinib, lestaurtinib, nilotinib, pazopanib, saracatinib, sorafenib, and sunitinib exhibited an increased inhibition of CYP3A after a 30-min preincubation with NADPH, as compared to no preincubation. Axitinib and vandetanib tested negative for time-dependent inhibition of CYP3A and CYP2C8, and bosutinib was the only inhibitor causing time-dependent inhibition of CYP2C8. The inhibitory mechanism by bosutinib was consistent with weak mechanism-based inhibition, and its inactivation variables KI and kinact were 54.8 μM and 0.018 1/min. As several of the tested inhibitors were reported to cause mechanism-based inactivation of CYP3A4 during the progress of this work, detailed experiments with these were not completed. However, lestaurtinib and saracatinib were identified as mechanism-based inhibitors of CYP3A. The KI and kinact of lestaurtinib and saracatinib were 30.7 μM and 0.040 1/min, and 12.6 μM and 0.096 1/min, respectively. Inhibition of CYP2C8 by bosutinib was predicted to have no clinical relevance, whereas therapeutic lestaurtinib and saracatinib concentrations were predicted to increase the plasma exposure to CYP3A-dependent substrates by ≤2.7-fold. The liability of kinase inhibitors to affect CYP450 enzymes by time-dependent inhibition may have long-lasting consequences and result in clinically relevant drug-drug interactions.Drug metabolism and disposition: the biological fate of chemicals 04/2014; · 3.74 Impact Factor