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

University of Helsinki, Helsinki, Uusimaa, Finland
Clinical Pharmacology &#38 Therapeutics (Impact Factor: 7.9). 05/2005; 77(5):404-14. DOI: 10.1016/j.clpt.2004.12.266
Source: PubMed


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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    • "The possibility of additive type of drug-drug interactions between the study drugs is ruled out; since, voriconazole by itself is devoid of any hypoglycemic activity. However, several documented reports reveal that oral hypoglycemic drugs when co-administered with oral anti-fungal drugs or any other drugs for the rational treatment of co-morbidities, it resulted in severe hypoglycemia.[717–19] The isoenzymes cytochrome (CYP), CYP2C9, CYP2C19 and CYP3A4 are responsible for metabolism of glibenclamide,[20] Similarly the other oral anti-diabetic drug pioglitazone is metabolized by microsomal isoenzymes CYP2C8, CYP3A4 and to lesser extent by CYP2C9.[2122] "
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    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.
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    • "Pioglitazone hydrochloride (Fig. 1), a thiazolidinedione is potent antidiabetic compound, which act by enhancing peripheral sensitivity to insulin can be taken without regard to meals. It is a substrate for CYP2C8 (39 %) and CYP3A4 (17 %), as well as several other CYP450 pathways and in vivo metabolism can be affected by inhibitors or inducers of CYP2C8 (Curtis, 2006) but no significant drug–drug interactions have been reported (Baldwin et al.., 1999; Niemi et al.., 2004; Jaakkola et al.., 2005). "
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    • "). The thiazolidinedione antidiabetic drugs rosiglitazone and pioglitazone inhibit OATP1B1 in vitro (Nozawa et al., 2004; Bachmakov et al., 2008), have been identified as potential OATP1B1 substrates in silico (Chang et al., 2005), and interact with the OATP1B1 inhibitor gemfibrozil in vivo (Niemi et al., 2003b; Jaakkola et al., 2005). However, gemfibrozil , or more specifically its glucuronide metabolite, is also a potent inhibitor of CYP2C8 in vivo (Backman et al., 2002; Niemi et al., 2003c; Shitara et al., 2004; Ogilvie et al., 2006), which could explain the effects. "
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