Pioglitazone is metabolised by CYP2C8 and CYP3A4 in vitro: potential for interactions with CYP2C8 inhibitors.
Article Details
- CitationCopy to clipboard
Jaakkola T, Laitila J, Neuvonen PJ, Backman JT
Pioglitazone is metabolised by CYP2C8 and CYP3A4 in vitro: potential for interactions with CYP2C8 inhibitors.
Basic Clin Pharmacol Toxicol. 2006 Jul;99(1):44-51. doi: 10.1111/j.1742-7843.2006.pto_437.x.
- PubMed ID
- 16867170 [ View in PubMed]
- Abstract
Our objective was to identify the cytochrome P450 (CYP) enzymes that metabolise pioglitazone and to examine the effects of the CYP2C8 inhibitors montelukast, zafirlukast, trimethoprim and gemfibrozil on pioglitazone metabolism in vitro. The effect of different CYP isoform inhibitors on the elimination of a clinically relevant concentration of pioglitazone (1 microM) and the formation of the main primary metabolite M-IV were studied using pooled human liver microsomes. The metabolism of pioglitazone by CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4 and CYP3A5 was investigated using human recombinant CYP isoforms. In particular, the inhibitors of CYP2C8, but also those of CYP3A4, markedly inhibited the elimination of pioglitazone and the formation of M-IV by HLM. Inhibitors selective to other CYP isoforms had a minor effect only. Of the recombinant isoforms, CYP2C8 (20 pmol/ml) metabolised pioglitazone markedly (56% in 60 min.), and also CYP3A4 had a significant effect (37% in 60 min.). Montelukast, zafirlukast, trimethoprim and gemfibrozil inhibited pioglitazone elimination in HLM with IC50 values of 0.51 microM, 1.0 microM, 99 microM and 98 microM, respectively, and the formation of the metabolite M-IV with IC50 values of 0.18 microM, 0.78 microM, 71 microM and 59 microM, respectively. In conclusion, pioglitazone is metabolised mainly by CYP2C8 and to a lesser extent by CYP3A4 in vitro. CYP2C9 is not significantly involved in the elimination of pioglitazone. The effect of different CYP2C8 inhibitors on pioglitazone pharmacokinetics needs to be evaluated also in vivo because, irrespective of their in vitro CYP2C8 inhibitory potency, their pharmacokinetic properties may affect the extent of interaction.
DrugBank Data that Cites this Article
- Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Pioglitazone Cytochrome P450 2C8 Protein Humans UnknownSubstrateInhibitorDetails Pioglitazone Cytochrome P450 3A4 Protein Humans UnknownSubstrateInducerDetails Zafirlukast Cytochrome P450 2C8 Protein Humans UnknownInhibitorDetails - Drug Reactions
Reaction Details Details Details Details Details Details Details Details
