Pharmacokinetics and metabolism of midazolam in chimeric mice with humanised livers

The pharmacokinetics and biotransformation of midazolam were investigated following single oral doses of 0.1, 1 and 10 mg/kg to chimeric mice with humanised livers (PXB mice) and to severe combined immunodeficient (SCID) mice used as controls.Pharmacokinetic analysis, on whole blood, revealed rapid absorption of the administered midazolam with a higher Cmax in PXB compared to SCID. The exposure to 1′-hydroxymidazolam was approximately 14-fold greater than to midazolam in the SCID mice and close to equivalent in the PXB mice. The metabolism of midazolam in SCID mice was faster than in the PXB mice such that pharmacokinetic data for midazolam in SCID mice could not be generated from the lowest dose in these animals.Both oxidative and conjugative metabolic pathways were identified in the PXB mice. All the major circulating metabolites observed in humans; 1′-hydroxymidazolam, 4′-hydroxymidazolam, 1′,4′-dihydroxymidazolam and 1′-hydroxymidazolam glucuronide, were detected in the blood of PXB mice. However, 4′-...