Pharmacokinetic Properties of CYP3A Substrate Midazolam Associated with Xenobiotic-Mediated CYP Induction in Inflammation Model Mice

Abstract

Inflammation can downregulate CYP isoforms and alter the pharmacokinetics of certain drugs. The expression of CYP isoforms is induced by the activation of nuclear receptors, including the pregnane X receptor (PXR). This study aimed to clarify the changes in the inducibility of CYP and in vivo relevance to pharmacokinetics in an inflammatory state. We investigated the changes in the mRNA expression of Cyp3a11 induced by pregnenolone-16α-carbonitrile (PCN), a rodent PXR agonist, in the liver and small intestine of inflammation model mice generated by injection of lipopolysaccharide (LPS). The systemic effects of inflammation on CYP induction were also investigated by measuring changes in the plasma concentration of midazolam, a CYP3A substrate. Cyp3a11 mRNA expression levels in the liver and small intestine of mice were decreased by LPS treatment and increased by PCN administration. Hepatic Cyp3a11 mRNA expression levels were significantly lower in LPS-and PCN-administered mice than in PCN-administered mice, whereas intestinal Cyp3a11 mRNA expression levels were significantly higher in LPS-and PCN-administered mice than in PCN-administered mice. The plasma concentration-time profiles and area under the concentration-time curve of midazolam and its metabolite 1'-hydroxymidazolam in LPS-and PCN-administered mice tended to be higher than those in PCNadministered mice. LPS-induced inflammation may suppress the increased metabolism of midazolam by PCN, which is consistent with the hepatic Cyp3a11 mRNA expression results. Therefore, CYP inducibility via PXR activation may be attenuated in an inflammatory state. Pharmacokinetic drug-drug interactions caused by CYP induction may be altered in patients with inflammation.