Purpose: To study the contribution of P-glycoprotein (P-gp) to the oral absorption of a substrate, tacrolimus, by comparing the extent and rate of bioavailability in normal and mdr1a knockout mice. Methods. Intravenous and oral (2 mg/kg) blood concentration data of tacrolimus in normal and knockout mice were obtained from a study by K. Yokogawa et al. in Pharm. Res. 16:1213-1218 (1999). Mean bioavailability (F), mean hepatic first-pass extraction ratio (Fh), mean bioavailability rates, mean oral clearance, and mean total hepatic intrinsic clearance were calculated using standard pharmacokinetic methods.
Results: The mean F of tacrolimus (an apparently highly permeable compound) was increased from 0.22 in normal mice to 0.72 in knockout mice. These values were consistent with mean predicted Eh (based on intravenous data) of 0.77 and 0.27 in normal and knockout mice, respectively. Great similarity in the relative bioavailability profile (such as short Tmax) between normal and knockout mice was also found. Mean oral clearance and mean total or unbound hepatic intrinsic clearance of tacrolimus in knockout mice were found to be about 10 times lower compared to those in normal mice.
Conclusions: The above results suggest an apparent lack of effect of P-gp on the gastrointestinal absorption of tacrolimus in normal mice under the study condition. It is postulated that the effect of P-gp on the rate and extent of oral absorption should be more pronounced for those more slowly or incompletely absorbed drugs (i.e., drugs with relatively low permeabilities) as illustrated by talinolol in humans. The clearance data also suggest a very dominant role of P-glycoprotein in controlling the rate of hepatic metabolism of tacrolimus in normal mice, and P-glycoprotein may serve as an effective efflux pump for direct transport of metabolites formed in hepatocytes into the blood circulation.