ISSN:
1573-904X
Keywords:
tacrolimus
;
P-glycoprotein
;
bioavailability
;
drug absorption
;
mice
Source:
Springer Online Journal Archives 1860-2000
Topics:
Chemistry and Pharmacology
Notes:
Abstract Purpose. To study the contribution of P-glycoprotein (P-gp) to the oralabsorption of a substrate, tacrolimus, by comparing the extent and rateof bioavailability in normal and mdr1a knockout mice. Methods. Intravenous and oral (2 mg/kg) blood concentration data oftacrolimus in normal and knockout mice were obtained from a studyby K. Yokogawa et al. in Pharm. Res. 16:1213-1218 (1999). Meanbioavailability (F), mean hepatic first-pass extraction ratio (Fh), meanbioavailability rates, mean oral clearance, and mean total hepaticintrinsic clearance were calculated using standard pharmacokinetic methods. Results. The mean F of tacrolimus (an apparently highly permeablecompound) was increased from 0.22 in normal mice to 0.72 in knockoutmice. These values were consistent with mean predicted Eh (based onintravenous data) of 0.77 and 0.27 in normal and knockout mice,respectively. Great similarity in the relative bioavailability profile (suchas short Tmax) between normal and knockout mice was also found. Meanoral clearance and mean total or unbound hepatic intrinsic clearance oftacrolimus in knockout mice were found to be about 10 times lowercompared to those in normal mice. Conclusions. The above results suggest an apparent lack of effect ofP-gp on the gastrointestinal absorption of tacrolimus in normal miceunder the study condition. It is postulated that the effect of P-gp onthe rate and extent of oral absorption should be more pronounced forthose more slowly or incompletely absorbed drugs (i.e., drugs withrelatively low permeabilities) as illustrated by talinolol in humans. Theclearance data also suggest a very dominant role of P-glycoprotein incontrolling the rate of hepatic metabolism of tacrolimus in normalmice, and P-glycoprotein may serve as an effective efflux pump fordirect transport of metabolites formed in hepatocytes into the bloodcirculation.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1023/A:1007573531947
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