Psychotropic drug-drug interactions involving P-glycoprotein

Multidrug resistance P-glycoprotein (P-gp; also known as MDR1 and ABCB1) is expressed in the luminal membrane of the small intestine and blood-brain barrier, and the apical membranes of excretory cells such as hepatocytes and kidney proximal tubule epithelia. P-gp regulates the absorption and elimination of a wide range of compounds, such as digoxin, paclitaxel, HIV protease inhibitors and psychotropic drugs. Its substrate specificity is as broad as that of cytochrome P450 (CYP) 3A4, which encompasses up to 50 % of the currently marketed drugs. There has been considerable interest in variations in the ABCB1 gene as predictors of the pharmacokinetics and/or treatment outcomes of several drug classes, including antidepressants and antipsychotics. Moreover, P-gp-mediated transport activity is saturable, and is subject to modulation by inhibition and induction, which can affect the pharmacokinetics, efficacy or safety of P-gp substrates. In addition, many of the P-gp substrates overlap with CYP3A4 substrates, and several psychotropic drugs that are P-gp substrates are also CYP3A4 substrates. Therefore, psychotropic drugs that are P-gp substrates may cause a drug interaction when P-gp inhibitors and inducers are coadministered, or when psychotropic drugs or other medicines that are P-gp substrates are added to a prescription. Hence, it is clinically important to accumulate data about drug interactions through studies on P-gp, in addition to CYP3A4, to assist in the selection of appropriate psychotropic medications and in avoiding inappropriate combinations of therapeutic agents. There is currently insufficient information available on the psychotropic drug interactions related to P-gp, and therefore we summarize the recent clinical data in this review.