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

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.

Intestinal absorption of novel-dipeptide prodrugs of saquinavir in rats

“…Broad substrate specificity of P-gp is a major factor responsible for subtherapeutic levels of various drugs in blood and tissues (Varma et al, 2003). A recent report suggests that presence of this efflux transporter on the brush border membrane of intestinal epithelium not only diminishes permeability of various therapeutic agents but also enhances the metabolism of these molecules by effluxing the drugs into the intestinal lumen or blood capillaries thereby increasing drug exposure to cellular as well as lumenal enzymes (Lown et al, 1997;Watkins, 1997;Ito et al, 1999).…”

Functional characterization of peptide transporters in MDCKII–MDR1 cell line as a model for oral absorption studies

“…Broad substrate specificity of P-gp is a major factor responsible for sub-therapeutic levels of various drugs in blood and tissues (Varma et al, 2003). Recent reports suggest that the presence of this efflux pump on the brush border membrane of intestinal epithelium not only diminishes permeability of various therapeutic agents but also enhances the metabolism of these molecules by effluxing the drug into the intestinal lumen or blood capillaries thereby increasing the drug exposure to cellular as well as luminal enzymes (Lown et al, 1997;Watkins, 1997;Ito et al, 1999). Several strategies have been employed to bypass or inhibit this efflux transporter and increase the oral bioavailability of such therapeutic agents.…”

Site-dependent contributions of P-glycoprotein and CYP3A to cyclosporin A absorption, and effect of dexamethasone in small intestine of mice

“…It is suggested that P-glycoprotein (P-gp) and/or CYP3A limit the oral bioavailability of digoxin, rifampin [4], vinblastine [5], dexamethasone tromethorphan [6], tacrolimus [7], sirolimus [8] and cyclosporin A [9,10]. Lown et al [11] suggested that P-glycoprotein…”