Drug Interactions Involving Renal Transport Mechanisms: An Overview

Abstract

The renal anatomy, physiology, and cellular mechanisms involved in tubular transport of organic acids (anions) and bases (cations) are reviewed. Drugs that are renally secreted are prone to significant and complex drug-drug interactions, and knowledge of the underlying mechanisms is important. Several clinical studies involving commonly used cationic drugs (e.g., cimetidine, trimethoprim, and procainamide) are cited as examples of drug interactions involving renal transport mechanisms.

Effect of Ranitidine on the Pharmacokinetics of Orally Administered Eprosartan, an Angiotensin II Antagonist, in Healthy Male Volunteers

“…Eprosartan is a zwitterion with pKa values of 4.11, 5.68, and 6.89, 7 and would theoretically be available for secretion by the organic anionic and cationic renal transport systems. 13 However, at physiologic pH, the species are primarily distributed as the unprotonated dicarboxyl groups (organic anion). Therefore, although ranitidine has been shown to inhibit the tubular secretion of a…”

Trimethoprim/Sulfamethoxazole Does Not Affect the Steady‐State Disposition of Indinavir

“…9 Indinavir sulfate also significantly increased the GM ratio of SMZ AUC 0-12h values (1.05; p = 0.039), although again this change was small and not felt to be clinically significant since the 90% CI (1.01, 1.09) was well within the interval (0.5, 2.0). 11 For the same reason, indinavir sulfate would not be expected to competitively inhibit the biliary excretion of SMZ. 10 In vitro data suggest that the majority of an SMZ dose undergoes hydroxylation (catalyzed by hepatic CYP2C9 isoforms) and acetylation to N4acetyl-SMZ (mediated by hepatic N-acetyltransferases), with a smaller percentage undergoing glucuronidation.…”

“…2 Steady-state AUC 0-8h , C max , and C 8h values of indinavir at this dose are 30,691 ± 11,407 nM•h, 12,617 ± 4037 nM, and 251 ± 178 nM, respectively. 8,9,11 A clinically important interaction is therefore unlikely even at the currently approved dose of indinavir sulfate. However, the pharmacokinetic profiles of indinavir sulfate and TMP/SMZ suggest that our study results are applicable to the concomitant administration of both agents at the currently recommended dosages.…”

“…7 Trimethoprim/sulfamethoxazole (TMP/SMZ) is a combination antimicrobial agent widely used in HIV seropositive patients for the prevention and treatment of Pneumocystis carinii pneumonia. [11][12][13][14] SMZ undergoes extensive hepatic biotransformation (primarily by CYP2C9) followed by renal and biliary excretion of the parent drug and metabolites. 9,10 TMP is a weak base eliminated primarily by glomerular filtration and renal tubular secretion.…”

“…[11][12][13][14] SMZ undergoes extensive hepatic biotransformation (primarily by CYP2C9) followed by renal and biliary excretion of the parent drug and metabolites. [7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22] This information is clinically relevant since many patients treated with indinavir sulfate will also be receiving TMP/SMZ. [17][18][19] This study, conducted in 12 healthy adult volunteers, was designed to investigate the safety profile and potential pharmacokinetic interaction between indinavir sulfate at a dose of 400 mg orally every 6 hours and TMP/SMZ.…”