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The orally active male contraceptive agent H2‐gamendazole interacts with organic anion transporting polypeptides expressed in human hepatocytes (1064.18)

The non‐hormonal male contraceptive H2‐gamendazole (H2‐GMZ) is a lonidamine derivative that has been shown to accumulate in rat testes at levels about 10 times higher than in the liver and other organs. Given that H2‐GMZ is an organic anion with a molecular weight of more than 400 Da, it could interact with Organic Anion Transporting Polypeptides (OATPs). Therefore, we wanted to test to what extent H2‐GMZ could interact with OATP1B1 and OATP1B3, two OATPs expressed in human hepatocytes. Uptake of the model substrates estradiol‐17β‐glucuronide, estrone‐3‐sulfate, taurocholate, and of pravastatin was measured in Chinese Hamster Ovary (CHO) cells expressing OATP1B1 or OATP1B3 in the absence and presence of H2‐GMZ. Furthermore, direct uptake of the fluorescent FITC‐H2‐GMZ and of the radiolabeled 3H‐H2‐GMZ was determined in wild‐type and OATP‐expressing CHO cells. Uptake of all OATP substrates was inhibited by H2‐GMZ in a concentration dependent way. Uptake of FITC‐H2‐GMZ was highest in OATP1B3‐expressing CHO cells followed by OATP1B1‐expressing CHO cells. However, when 3H‐H2‐GMZ was used as a substrate, no OATP‐mediated uptake could be detected which is consistent with the in vivo animal data that liver uptake is minimal. Given that fluorescein is a substrate for both OATPs, we assume that in the case of FITC‐H2‐GMZ the fluorescent moiety is recognized by the transporters. Thus, although H2‐GMZ inhibits OATP‐mediated uptake of several substrates in a concentration dependent way, it does not seem to be a good substrate for OATP1B1 and OATP1B3 and liver accumulation in humans is unlikely.