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

TLDR

Interpatient variability in oral cyclosporine clearance is partly due to liver CYP3A4, and small‑bowel CYP3A4 and P‑glycoprotein have also been identified. The study aimed to determine the contribution of intestinal CYP3A4 and P‑glycoprotein to cyclosporine pharmacokinetics. Oral pharmacokinetics were measured in 25 kidney‑transplant recipients whose liver CYP3A4 activity was quantified by an intravenous ^14C‑erythromycin breath test and who had small‑bowel biopsies for CYP3A4 and P‑glycoprotein assessment. Liver CYP3A4 activity explained 56 % of the variability in oral clearance and 32 % of peak concentration, while intestinal P‑glycoprotein accounted for 17 % of clearance and 30 % of peak concentration variability; intestinal CYP3A4 had no effect, indicating P‑glycoprotein is a key first‑pass elimination factor and may mediate previously attributed CYP3A4 interactions. Clinical Pharmacology & Therapeutics 1997; 62:248–260.

Abstract

Interpatient differences in the oral clearance of cyclosporine (INN, ciclosporin) have been partially attributed to variation in the activity of a single liver enzyme termed CYP3A4. Recently it has been shown that small bowel also contains CYP3A4, as well as P-glycoprotein, a protein able to transport cyclosporine. To assess the importance of these intestinal proteins, the oral pharmacokinetics of cyclosporine were measured in 25 kidney transplant recipients who each had their liver CYP3A4 activity quantitated by the intravenous [14C-N-methyl]-erythromycin breath test and who underwent small bowel biopsy for measurement of CYP3A4 and P-glycoprotein. Forward multiple regression revealed that 56% (i.e., r2 = 0.56) and 17% of the variability in apparent oral clearance [log (dose/area under the curve)] were accounted for by variation in liver CYP3A4 activity (p < 0.0001) and intestinal P-glycoprotein concentration (p = 0.0059), respectively. For peak blood concentration, liver CYP3A4 activity accounted for 32% (p = 0.0002) and P-glycoprotein accounted for an additional 30% (p = 0.0024) of the variability. Intestinal levels of CYP3A4, which varied tenfold, did not appear to influence any cyclosporine pharmacokinetic parameter examined. We conclude that intestinal P-glycoprotein plays a significant role in the first-pass elimination of cyclosporine, presumably by being a rate-limiting step in absorption. Drug interactions with cyclosporine previously ascribed to intestinal CYP3A4 may instead be mediated by interactions with intestinal P-glycoprotein. Clinical Pharmacology & Therapeutics (1997) 62, 248–260; doi: