Abstract
BackgroundRanitidine (Zantac®) is a H2-receptor antagonist commonly used for the treatment of acid-related gastrointestinal diseases. Ranitidine was reported to be a substrate of the organic cation transporters OCT1 and OCT2. The hepatic transporter OCT1 is highly genetically variable. Twelve major alleles confer partial or complete loss of OCT1 activity. The effects of these polymorphisms are highly substrate-specific and therefore difficult to predict. The renal transporter OCT2 has a common polymorphism, Ala270Ser, which was reported to affect OCT2 activity.AimIn this study we analyzed the effects of genetic polymorphisms in OCT1 and OCT2 on the uptake of ranitidine and on its potency to inhibit uptake of other drugs.Methods and resultsWe characterized ranitidine uptake using HEK293 and CHO cells stably transfected to overexpress wild type OCT1, OCT2, or their naturally occurring allelic variants. Ranitidine was transported by wild-type OCT1 with a Km of 62.9 μM and a vmax of 1125 pmol/min/mg protein. Alleles OCT1*5, *6, *12, and *13 completely lacked ranitidine uptake. Alleles OCT1*2, *3, *4, and *10 had vmax values decreased by more than 50%. In contrast, OCT1*8 showed an increase of vmax by 25%. The effects of OCT1 alleles on ranitidine uptake strongly correlated with the effects on morphine uptake suggesting common interaction mechanisms of both drugs with OCT1. Ranitidine inhibited the OCT1-mediated uptake of metformin and morphine at clinically relevant concentrations. The inhibitory potency for morphine uptake was affected by the OCT1*2 allele. OCT2 showed only a limited uptake of ranitidine that was not significantly affected by the Ala270Ser polymorphism.ConclusionsWe confirmed ranitidine as an OCT1 substrate and demonstrated that common genetic polymorphisms in OCT1 strongly affect ranitidine uptake and modulate ranitidine’s potential to cause drug-drug interactions. The effects of the frequent OCT1 polymorphisms on ranitidine pharmacokinetics in humans remain to be analyzed.
Highlights
Ranitidine (Zantac1) is a histamine H2-receptor antagonist which is used for the treatment of acid-related gastrointestinal diseases such as pyrosis and gastric ulcers
Dulbecco’s Modified Eagle Medium (DMEM), Roswell Park Memorial Institute (RPMI) 1640, Hank’s Buffered Salt Solution (HBSS), and additives used for cell culturing were obtained from Life Technologies
To evaluate ranitidine as a substrate of organic cation transporters 1 (OCT1) we compared the intracellular accumulation of ranitidine between HEK293 cells overexpressing wild type OCT1 and control cells transfected with the empty vector pcDNA5
Summary
Ranitidine (Zantac1) is a histamine H2-receptor antagonist which is used for the treatment of acid-related gastrointestinal diseases such as pyrosis (heartburn) and gastric ulcers. Some adverse reactions were reported in ranitidine users, including headache and upper respiratory tract infections [5]. Meta-analyses of controlled clinical trials failed to show a direct relation of any adverse effects with ranitidine administration [6]. Ranitidine (Zantac®) is a H2-receptor antagonist commonly used for the treatment of acidrelated gastrointestinal diseases. Ranitidine was reported to be a substrate of the organic cation transporters OCT1 and OCT2. Twelve major alleles confer partial or complete loss of OCT1 activity. The effects of these polymorphisms are highly substrate-specific and difficult to predict. The renal transporter OCT2 has a common polymorphism, Ala270Ser, which was reported to affect OCT2 activity
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