Changes in P-glycoprotein during Treatment with Anti-cancer Drug and its Influence on Pharmacokinetics and Pharmacological Effects

Abstract

1） それらの過程を変動させる因子として，薬物代謝 酵素，薬物トランスポーター並びに血漿タンパク質 結合率などが挙げられる． 2, 3） 各種医薬品の添付文書 やインタビューフォームに記載されているように， 薬物の体内動態における cytochrome P-450 （ CYP ） などの薬物代謝酵素の役割については広く認識さ れている．一方，近年になって，薬物トランスポー ター分子の同定並びにその機能解析が急速に進ん だ結果，薬物トランスポーターは ADME のすべて の過程に関与し，薬物の体内動態を決定する重要 な因子であることが明らかになってきた． 1, 4） 薬物トランスポーターは，solute carrier （ SLC ） および adenosine-5＇-triphosphate (ATP)-binding cassette （ ABC ）トランスポーターの 2 つに大別され， 5） 全 身循環血中濃度や標的組織における薬物濃度を制 御し，薬理作用・毒性の発現と密接に関係してい る．従って，薬物トランスポーターが種々の薬物 医療薬学 40(4) 193―207 (2014) In pharmaceutical therapy, the onset of pharmacological and adverse effects of drugs varies widely among individuals. Since these effects are mostly dependent on the blood level of each drug, it is particularly important to monitor and regulate those levels after drug administration. Factors influencing the pharmacokinetics and pharmacodynamics of drugs include drug transporters, drug metabolizing enzymes and the plasma protein-binding ratio. Among these factors, we focused on P-glycoprotein (P-gp), a drug efflux transporter. The expression and function of P-gp are reported to alter under several pathological conditions and by administrating some foods or substrate drugs for P-gp. In this mini-review, we introduce alterations in the expression and functional activity of P-gp by anti-cancer drugs, most of which are P-gp substrates, in addition to their mechanism of action. In tumorous or healthy tissues, the expression and function of P-gp were increased by chronic exposure to anti-cancer drugs. A large number of previous studies have proposed that not only various transcriptional factors for P-gp but also post-translational factors such as ezrin/radixin/moesin are involved in changes in P-gp. The expression and function of P-gp seem to be altered during anti-cancer treatment possibly through the above pathways, which may in turn affect the pharmacokinetics and pharmacodynamics of drugs. Therefore, the response should take into account the kinds of drugs each patient uses and their status of P-gp expression and function in clinical pharmacotherapy.