Coordinated Roles of Pregnane X Receptor and Constitutive Androstane Receptor in Autoinduction of Voriconazole Metabolism in Mice

Abstract

The antifungal efficacy of voriconazole (VRC) differs among host species, with potent efficacy in humans but less in rodents. We investigated the possible involvement of pregnane X receptor (PXR) and constitutive androstane receptor (CAR) in the speciesspecific efficacy of VRC through pharmacokinetic analyses using genetically modified mice and primary human hepatocytes. VRC (30 mg/kg) was orally administered to wild-type, Pxr-null, Car-null, and Pxr-and Car-null (Pxr/Car-null) mice for 7 days. Hepatic VRC metabolism was significantly increased by VRC administration, and the elimination rates of plasma VRC were much higher on day 7 than on day 1 in wild-type mice. This autoinduction was also observed in Pxr-null and Car-null mice but not in Pxr/Car-null mice, suggesting coordinated roles of PXR and CAR in the autoinduction of VRC metabolism in mice. Hepatic Cyp3a11 mRNA levels were increased by VRC administration, hepatic metabolic activities for VRC were correlated with CYP3A activities, and the induced VRC metabolism was inhibited by ketoconazole (a CYP3A inhibitor). In primary human hepatocytes, VRC barely increased mRNA levels of CYP3A4 and CYP2B6 (human PXR/CAR target genes) at its therapeutic concentrations. In conclusion, these results suggest that VRC is metabolized mainly by CYP3A11 in mouse livers and that PXR-and CAR-mediated CYP3A11 induction, namely, autoinduction of VRC metabolism, is a primary reason for the ineffectiveness of VRC in mice. A limited ability of VRC to activate human PXR/CAR at its clinical concentration might explain the VRC efficacy in humans. Therefore, the ability to activate PXR/CAR might determine the VRC efficacy in different mammalian species.

Voriconazole therapeutic drug monitoring: results of a prematurely discontinued randomized multicenter trial

“…It is, however, of interest that few studies have been performed to assess serial VOR levels over long periods of time. The potential of auto‐induction of metabolism has been postulated in humans , and studied in greater depth in rodents, the latter of which demonstrate auto‐induction by mechanisms that involve pregnane X receptor‐ and constitutive androstane receptor‐mediated induction of CYP3A11 . However, this mechanism is thought to be species‐specific and not involved in human metabolism of the drug.…”

Autoinduction of Voriconazole Metabolism in a Child with Invasive Pulmonary Aspergillosis

“…In human hepatocyte studies, voriconazole was not able to induce CYP3A4 or CYP2B6 to the extent that rifampin and phenobarbital are able to induce these enzymes (rifampin is a known human PXR activator, and phenobarbital is a known human CAR activator) . Voriconazole was also unable to induce CYP2C19 in human hepatocytes . It is hypothesized that clinical doses used in humans are generally lower than doses used in animal studies and therefore do not cause the same induction response seen in animals .…”

“…Activation of the nuclear receptors pregnane X‐receptor (PXR) and constitutive androstane receptor (CAR), which are responsible for regulating the expression of many phase I and II drug‐metabolizing enzymes, has been suggested as the underlying mechanism for voriconazole autoinduction of metabolism . PXR is primarily associated with the regulation of CYP3A genes, whereas CAR predominantly regulates CYP2B and CYP2C genes .…”

Advances in Reptile Clinical Therapeutics

“…Metabolism varies among species, and autoinduction of metabolism by cytochrome P450 3A11 occurs in mice but not humans. 79 Voriconazole is eliminated primarily via hepatic metabolism; less than 2% of the oral dose is excreted unchanged in the urine of humans, and more than 80% of the metabolites are recovered in the urine. Doses of voriconazole should be adjusted according to plasma levels of the drug in patients with hepatic insufficiency.…”