A physiologically based kidney model for the renal clearance of ranitidine and the interaction with cimetidine and probenecid in the dog

Boom, S; Meyer, Ineke; Wouterse, Alfons C.; Rüssel, Frans G. M.

doi:10.1002/(sici)1099-081x(199804)19:3<199::aid-bdd1>3.0.co;2-2

Cited by 17 publications

(5 citation statements)

References 18 publications

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“…Interestingly, also organic anion transporters from the SLC22 family that are basolaterally expressed in the human kidney—OAT1, OAT2, and OAT3—were shown to transport ranitidine in vitro [ 72 ]. Furthermore, co-administration of the OAT-inhibitor probenecid in dogs reduced ranitidine renal clearances by two-fold and basolateral uptake by four-fold [ 73 ]. It will be interesting to evaluate experimentally the role of these transporters in the renal elimination of ranitidine in humans.…”

Section: Discussionmentioning

confidence: 99%

Effects of genetic polymorphisms on the OCT1 and OCT2-mediated uptake of ranitidine

et al. 2017

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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.

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Section: Discussionmentioning

confidence: 99%

Effects of genetic polymorphisms on the OCT1 and OCT2-mediated uptake of ranitidine

et al. 2017

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“…Recent investigations suggest that cimetidine and famotidine are substrates of the highly expressed renal organic anion transporter hOAT3 (SLC22A8) (Cha et al, 2001;Motohashi et al, 2004), whereas ranitidine has been identified as a substrate of the rat isoform rOAT3 (Nagata et al, 2004). Although it is not known whether ranitidine is also a substrate of hOAT3, probenecid, an organic anion transporter inhibitor, reduces the renal clearance of ranitidine in the dog (Boom et al, 1998) as well as that of famotidine in humans (Inotsume et al, 1990). Therefore, multiple transporters, including hOCT2 and hOAT3, are likely involved in the renal excretion of ranitidine and famotidine in humans.…”

Section: Discussionmentioning

confidence: 99%

Differential Substrate and Inhibitory Activities of Ranitidine and Famotidine toward Human Organic Cation Transporter 1 (hOCT1; SLC22A1), hOCT2 (SLC22A2), and hOCT3 (SLC22A3)

Bourdet

Pritchard

Thakker³

2005

J Pharmacol Exp Ther

100

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Human organic cation transporters (hOCTs) are expressed in organs of drug absorption and elimination and play an important role in the uptake and elimination of xenobiotics. The purpose of this study was to evaluate the substrate and inhibitory activity of the H 2 -receptor antagonists ranitidine and famotidine toward hOCTs and to determine the hOCT isoforms involved in the absorption and elimination of these compounds in humans. Inhibition and substrate specificity of hOCT1, hOCT2, and hOCT3 for ranitidine and famotidine were elucidated in cRNA-injected Xenopus laevis oocytes. Ranitidine and famotidine exhibited similarly potent inhibition of [ 3 H]1-methyl-4-phenyl pyridinium uptake into hOCT1-expressing (IC 50 ϭ 33 and 28 M, respectively) and hOCT2-expressing oocytes (IC 50 ϭ 76 and 114 M, respectively). Famotidine exhibited potent inhibition of hOCT3; in contrast, ranitidine was a moderately weak inhibitor (IC 50 ϭ 6.7 and 290 M, respectively).[ 3 H]Ranitidine uptake was stimulated by hOCT1 (K m ϭ 70 Ϯ 9 M) and to a much smaller extent by hOCT2. No stimulation of [ 3 H]ranitidine uptake was observed in hOCT3-expressing oocytes. trans-Stimulation and electrophysiology studies suggested that famotidine also is an hOCT1 substrate and exhibits poor or no substrate activity toward hOCT2 and hOCT3. Thus, hOCT1, which is expressed in the intestine and liver, is likely to play a major role in the intestinal absorption and hepatic disposition of ranitidine and famotidine in humans, whereas hOCT2, the major isoform present in the kidney, may play only a minor role in their renal elimination. Famotidine seems to be one of the most potent inhibitors of hOCT3 yet identified.The H 2 -receptor antagonists ranitidine and famotidine (Fig.

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“…Clearance data for other species (mice, rabbits, or monkeys) were also obtained for some drugs to apply an allometric scaling approach. The compounds, listed in Table 1, were selected from an extensive range to include compounds with various structures, pharmacological activities, and pharmacokinetic characteristics 6,10–61. Some drugs are mainly eliminated through renal excretion as unchanged forms, whereas some are extensively metabolized.…”

Section: Methodsmentioning

confidence: 99%

Prediction of Human Clearance from Animal Data and Molecular Structural Parameters using Multivariate Regression Analysis

Wajima

Fukumura

Yano

et al. 2002

Journal of Pharmaceutical Sciences

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A physiologically based kidney model for the renal clearance of ranitidine and the interaction with cimetidine and probenecid in the dog

Cited by 17 publications

References 18 publications

Effects of genetic polymorphisms on the OCT1 and OCT2-mediated uptake of ranitidine

Effects of genetic polymorphisms on the OCT1 and OCT2-mediated uptake of ranitidine

Differential Substrate and Inhibitory Activities of Ranitidine and Famotidine toward Human Organic Cation Transporter 1 (hOCT1; SLC22A1), hOCT2 (SLC22A2), and hOCT3 (SLC22A3)

Prediction of Human Clearance from Animal Data and Molecular Structural Parameters using Multivariate Regression Analysis

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