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Limited role of P-glycoprotein in the intestinal absorption of cyclosporin A.

The contribution of P-glycoprotein (P-gp) to the intestinal absorption of cyclosporin A (CsA) was investigated by comparing the in vivo pharmacokinetics of CsA in P-gp knockout mice versus wild-type mice following both oral and intravenous administration and by examining the transport of CsA across Caco-2 cell monolayers. The apparent oral bioavailability of CsA in P-gp knockout mice was 1.55-fold larger than in wild-type mice, leading to an apparent absolute bioavailability of 41.8%. A concentration dependent efflux transport of CsA across Caco-2 cell monolayers was found, which exhibited saturation at a CsA concentration of 1 muM. These results suggest that the involvement of P-gp in the intestinal absorption of CsA is not as profound as was previously thought.