P‐glycoprotein and Drug Therapy in Organ Transplantation

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Abstract
The role of multidrug resistance and P‐glycoprotein (P‐gp) in the development of drug‐resistant tumor cells has been extensively studied. As more knowledge on the physiological functions of P‐gp has accumulated, the effects of P‐gp modulation on the pharmacokinetics and the pharmacodynamics of many drugs have become apparent. Solid organ transplant recipients receive numerous medications that are substrates for P‐gp. The objective of this review is to discuss the effects of P‐gp modulation on the pharmacokinetics and the pharmacodynamics of immunosuppressive agents such as cyclosporine, tacrolimus, sirolimus, and corticosteroids. Pharmacokinetic alterations may occur in drug absorption since P‐gp is in the small bowel, in drug distribution since P‐gp functions in the blood‐brain barrier, in drug metabolism since P‐gp and cytochrome P450 3A have linked functions, and in drug elimination since P‐gp is in the bile canaliculi and renal tubules. A link between P‐gp and organ rejection has been speculated since upregulation of the P‐gp pump may restrict immunosuppressant drug entry into immunocompetent cells. A further understanding of P‐gp regulation upon chronic exposure to P‐gp substrates and inhibitors and the potential administration of selective P‐gp inhibitors will enhance our ability to use potent immunosuppressive drugs in organ transplant patients.