Role of intestinal P‐glycoprotein (mdr1) in interpatient variation in the oral bioavailability of cyclosporine

摘要: Interpatient differences in the oral clearance of cyclosporine (INN, ciclosporin) have been partially attributed to variation activity a single liver enzyme termed CYP3A4. Recently it has shown that small bowel also contains CYP3A4, as well P-glycoprotein, protein able transport cyclosporine. To assess importance these intestinal proteins, pharmacokinetics were measured 25 kidney transplant recipients who each had their CYP3A4 quantitated by intravenous [14C-N-methyl]-erythromycin breath test and underwent biopsy for measurement P-glycoprotein. Forward multiple regression revealed 56% (i.e., r2 = 0.56) 17% variability apparent [log (dose/area under curve)] accounted (p < 0.0001) P-glycoprotein concentration 0.0059), respectively. For peak blood concentration, 32% 0.0002) an additional 30% 0.0024) variability. Intestinal levels which varied tenfold, did not appear influence any pharmacokinetic parameter examined. We conclude plays significant role first-pass elimination cyclosporine, presumably being rate-limiting step absorption. Drug interactions with previously ascribed may instead be mediated