OCT1 Deficiency Affects Hepatocellular Concentrations and Pharmacokinetics of Cycloguanil, the Active Metabolite of the Antimalarial Drug Proguanil

Abstract

Cycloguanil, the active metabolite of proguanil, acts on malaria schizonts in erythrocytes and hepatocytes. We analyzed the impact of the organic cation transporter OCT1 on hepatocellular uptake and pharmacokinetics of proguanil and cycloguanil. OCT1 transported both proguanil and cycloguanil. Common variants OCT1*3 and OCT1*4 caused a substantial decrease and OCT1*5 and OCT1*6 complete abolishment of proguanil uptake. In 39 healthy subjects, low-activity variants OCT1*3 and OCT1*4 had only minor effects on proguanil pharmacokinetics. However, both, cycloguanil area under the time-concentration curve and the cycloguanil-to-proguanil ratio were significantly dependent on number of these low-functional alleles (P = 0.02 for both). Together, CYP2C19, CYP3A5, OCT1 polymorphisms, and sex accounted for 61% of the variation in the cycloguanil-to-proguanil ratio. Most importantly, in vitro OCT1 inhibition caused a fivefold decrease of intracellular cycloguanil concentrations in primary human hepatocytes. In conclusion, OCT1-mediated uptake is a limiting step in bioactivation of proguanil, and OCT1 polymorphisms may affect proguanil efficacy against hepatic malaria schizonts.

Variability and Heritability of Thiamine Pharmacokinetics With Focus on OCT1 Effects on Membrane Transport and Pharmacokinetics in Humans

“…Apparently, it is not always possible to predict from in vitro experiments or from genetically modified mice whether or not human pharmacokinetics of an OCT1 substrate is dependent on OCT1 genotypes. Similar as with thiamine, also pharmacokinetics of some other prototypical substrates of OCT1 like metformin or proguanil did not depend in a significant fashion on OCT1 genotypes, although intrahepatic metformin concentrations and pharmacodynamics did depend on OCT1 genotypes . In the case of thiamine, several other organs also contribute to storage of thiamine and its phosphate esters even more than the liver .…”

Effects of proton pump inhibitors, esomeprazole and vonoprazan, on the disposition of proguanil, a CYP2C19 substrate, in healthy volunteers

“…Recently, Matthaei et al . reported that OCT1 allele showing reduced transport activity is associated with lower cycloguanil‐to‐proguanil ratio . Thus, this offers a possibility of OCT1 inhibition by vonoprazan as the underlying mechanism.…”

Dysregulation of solute carrier transporters in malaria‐infected pregnant mice

“…For example, changes in the expression of OCT1 could impact the hepatic uptake of its substrate, the antimalarial quinine, which is largely metabolized by the liver . Furthermore, OCT1 deficiency has been shown to significantly decrease hepatic uptake of the antimalarial drug proguanil, which is metabolized by the liver to its active metabolite, cycloguanil . Thus, decreased hepatic OCT1 expression could significantly hamper the efficacy of proguanil antimalarial therapy.…”

“…[32][33][34] We ob- proguanil, which is metabolized by the liver to its active metabolite, cycloguanil. 39 Thus, decreased hepatic OCT1 expression could significantly hamper the efficacy of proguanil antimalarial therapy. Downregulation of OCT1 could also alter the hepatic uptake of endogenous substrates including choline and agmatine, a metabolite of L-arginine.…”