Effects of gemfibrozil, itraconazole, and their combination on the pharmacokinetics of pioglitazone.

Department of Clinical Pharmacology, PO Box 340, FIN-00290 HUS, Finland.
Clinical Pharmacology &#38 Therapeutics (Impact Factor: 6.85). 05/2005; 77(5):404-14. DOI: 10.1016/j.clpt.2004.12.266
Source: PubMed

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.

  • [Show abstract] [Hide abstract]
    ABSTRACT: STUDY OBJECTIVES: To determine the influence of the Cytochrome P450 (CYP) 2C8*2 polymorphism on pioglitazone pharmacokinetics in healthy African-American volunteers. DESIGN: Prospective, open-label, single-dose pharmacokinetic study. SETTING: University of Colorado Hospital Clinical and Translational Research Center. PARTICIPANTS: Healthy African-American volunteers between 21 and 60 years of age were enrolled in the study based on CYP2C8 genotype: CYP2C8*1/*1 (9 participants), CYP2C8*1/*2 (7 participants), and CYP2C8*2/*2 (1 participant). INTERVENTION: Participants received a single 15-mg dose of pioglitazone in the fasted state, followed by a 48-hour pharmacokinetic study. MEASUREMENTS AND MAIN RESULTS: Plasma concentrations of pioglitazone and its M-III (keto) and M-IV (hydroxy) metabolites were compared between participants with the CYP2C8*1/*1 genotype and CYP2C8*2 carriers. Pioglitazone area under the plasma concentration-time curve (AUC)0-∞ and half-life (t1/2 ) did not differ significantly between CYP2C8*1/*1 and CYP2C8*2 carriers (AUC0-∞ 7331 ± 2846 vs 10431 ± 5090 ng*h/ml, p=0.15, t1/2 7.4 ± 2.7 vs 10.5 ± 4.0 h, p=0.07). M-III and M-IV AUC0-48 also did not differ significantly between genotype groups. However, the M-III:pioglitazone AUC0-48 ratio was significantly lower in CYP2C8*2 carriers than CYP2C8*1 homozygotes (0.70 ± 0.15 vs 1.2 ± 0.37, p=0.006). Similarly, CYP2C8*2 carriers had a significantly lower M-III:M-IV AUC0-48 ratio than participants with the CYP2C8*1/*1 genotype (0.82 ± 0.26 vs 1.22 ± 0.26, p=0.006). CONCLUSION: These data suggest that CYP2C8*2 influences pioglitazone pharmacokinetics in vivo, particularly the AUC0-48 ratio of M-III:parent drug, and the AUC0-48 ratio of M-III:M-IV. Larger studies are needed to further investigate the impact of CYP2C8*2 on the pharmacokinetics of CYP2C8 substrates in individuals of African descent.
    Pharmacotherapy 05/2013; · 2.31 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The objective was to study the of drug-drug interaction between voriconazole and oral hypoglycemic agents in normal and alloxan induced diabetic rats. The study was designed in two phases. In the first phase, influence of glibenclamide (0.45 mg/kg, p.o.) and pioglitazone (2.7 mg/kg, p.o. once daily) on blood glucose levels in normoglycemic rats was studied and then influence of voriconazole (18 mg/kg, p.o. twice daily.) pre-treatment on the hypoglycemic activity studied. Simultaneously the influence of voriconazole treatment for seven consecutive days (per se effect) on blood glucose levels was also studied in normoglycemic rats. In the second phase of the study alloxan-induced diabetic rats were used to find out the influence of voriconazole pre-treatment on glibenclamide and pioglitazone induced hypoglycemic effect in pathophysiological condition. Blood samples were collected from retro orbital plexus at regular intervals of 0.0, 0.5, 1.0, 2.0, 4.0, 8.0, 12.0, 18.0 and 24.0 h after drug treatment. All the blood samples were analyzed for plasma glucose by glucose oxidase peroxidase method (GOD/POD). The therapeutic dose of voriconazole potentiates the hypoglycemic activity of glibenclamide and pioglitazone both in normoglycemic and diabetic rats respectively. The results indicate that the dose of oral hypoglycemic agents needs to be adjusted if co-administered with voriconazole.
    Indian Journal of Pharmacology 01/2013; 45(2):155-158. · 0.58 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The identification, prevention, and solution of drug interactions are a critical aspect to achieved desired pharmacotherapy goals. The purpose of this review was to organize information about drug interactions, and to develop an approach to identify and evaluate drug interactions considered clinically relevant. Data for this review were identified by search of MEDLINE and PubMed and references cited in relevant articles. «Drug interactions» plus «clinical relevance», «clinically relevant» or «significantly relevant» were searched in titles or in abstracts. Only papers published in English and Spanish from January of 1996 to June of 2006 and in humans were reviewed. We reviewed the type and mechanism of drug interactions, and we highlight those associated to changes in the systemic clearance or in the bioavailability. So, we provide an approach to evaluate and use the clinical relevance of drug interactions complemented with a classification based on the severity and probability of its occurrence.
    Medicina Clinica - MED CLIN. 01/2007; 129(1):27-35.