PHARMACOKINETIC DRUG-DRUG INTERACTIONS MEDIATED BY ORGANIC CATION TRANSPORTERS: ARE ANTIMALARIAL DRUGS SIGNIFICANTLY AFFECTED?

Abstract

A clear understanding of all the processes that influence drug disposition is important to enable a prediction of pharmacokinetic drug interactions. Xenobiotics are transported across bio-membranes and the process is mediated by various membrane transporters which include “Organic Cation Transporters” (OCTs). OCTs are specifically involved in the transport of several molecules that have positive charges in vivo and these include a wide variety of weakly basic drugs.As several antimalarial drugs are weakly basic and can be cationic in biological fluids, the contribution of OCTs to the drug disposition appears to be underestimated because most studies on the pharmacokinetic drug interaction with antimalarial drugs are focused on the interactions at the sites of drug metabolism. This review provides an update on the significance of OCTs on the pharmacokinetic disposition of antimalarial agents with a view to identifying potentials for drug interactions that could involve concurrently administered drugs which are either inhibitors or substrates of OCTs. A very significant likelihood exists for concurrent use of antimalarial drugs with other medicines because of the occurrence of comorbidities with malaria. There are limited studies on antimalarial pharmacokinetic drug-drug interaction studies in which role of OCTs are investigated. From the literature, and using in vitro studies, the following antimalarial drugs, chloroquine, piperaquine, proguanil, and cycloguanil have been reported to be substrates of different OCTs while tafenoquine, pyrimethamine, trimethoprim, quinine, and mefloquine were shown to be inhibitors. Atovaquone and artesunate were shown not to be substrates and did not demonstrate any inhibitory potency. This information provide basis for prediction of any potential interaction between antimalarial drugs and other co-administered medicines which are inhibitors/substrates of the transporter proteins. Peer Review History: Received 6 February 2024; Revised 15 March 2024; Accepted 26 April; Available online 15 May 2024 Academic Editor: Dr. Nuray Arı, Ankara University, Turkiye, ari@ankara.edu.tr Average Peer review marks at initial stage: 6.5/10 Average Peer review marks at publication stage: 7.5/10 Reviewers: Dr. George Zhu, Tehran University of Medical Sciences, Tehran, Iran, sansan4240732@163.com Dr. Bilge Ahsen KARA, Ankara Gazi Mustafa Kemal Hospital, Turkey, ahsndkyc@gmail.com