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OCT 1 Deficiency Affects Hepatocellular Concentrations and Pharmacokinetics of Cycloguanil, the Active Metabolite of the Antimalarial Drug Proguanil
Author(s) -
Matthaei Johannes,
Seitz Tina,
Jensen Ole,
Tann Annabelle,
Prukop Thomas,
Tadjerpisheh Sina,
Brockmöller Jürgen,
Tzvetkov Mladen V.
Publication year - 2019
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1002/cpt.1128
Subject(s) - proguanil , pharmacokinetics , pharmacology , metabolite , organic cation transport proteins , active metabolite , chemistry , plasmodium falciparum , malaria , medicine , transporter , biochemistry , immunology , gene
Cycloguanil, the active metabolite of proguanil, acts on malaria schizonts in erythrocytes and hepatocytes. We analyzed the impact of the organic cation transporter OCT 1 on hepatocellular uptake and pharmacokinetics of proguanil and cycloguanil. OCT 1 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, CYP 2C19 , CYP 3A5 , OCT 1 polymorphisms, and sex accounted for 61% of the variation in the cycloguanil‐to‐proguanil ratio. Most importantly, in vitro OCT 1 inhibition caused a fivefold decrease of intracellular cycloguanil concentrations in primary human hepatocytes. In conclusion, OCT 1‐mediated uptake is a limiting step in bioactivation of proguanil, and OCT 1 polymorphisms may affect proguanil efficacy against hepatic malaria schizonts.