Effects of Renal Impairment on the Pharmacokinetics of Morinidazole: Uptake Transporter-Mediated Renal Clearance of the Conjugated Metabolites

Abstract

Morinidazole is a novel 5-nitroimidazole antimicrobial drug that undergoes extensive metabolism in humans via N ؉ -glucuronidation (N ؉ -glucuronide of S-morinidazole [M8-1] and N ؉ -glucuronide of R-morinidazole [M8-2]) and sulfation (sulfate conjugate of morinidazole [M7]). Our objectives were to assess the effects of renal impairment on the pharmacokinetics (PK) of morinidazole and to elucidate the potential mechanisms. In this parallel-group study, healthy subjects and patients with severe renal impairment received an intravenous infusion of 500 mg of morinidazole. Plasma and urine samples were collected and analyzed. The areas under the plasma concentration-time curves (AUC) for M7, M8-1, and M8-2 were 15.1, 20.4, and 17.4 times higher, respectively, in patients with severe renal impairment than in healthy subjects, while the AUC for morinidazole was 1.5 times higher. The urinary recovery of the major metabolites was not significantly different between the two groups over 0 to 48 h, but the renal clearances of M7, M8-1, and M8-2 in patients were 85.3%, 92.5%, and 92.2% lower, respectively. In vitro transporter studies revealed that M7 is a substrate for organic anion transporter 1 (OAT1) and OAT3 (K m ‫؍‬ 28.6 and 54.0 M, respectively). Only OAT3 transported M8-1 and M8-2. Morinidazole was not a substrate for the transporter-transfected cells examined. These results revealed that the function or activity of renal uptake transporters might be impaired in patients with severe renal impairment, which accounted for dramatically increased plasma exposure and reduced renal clearance of the conjugated metabolites of morinidazole, the substrates of renal transporters in patients. It will help clinicians to adjust the dose in patients with severe renal impairment and to predict possible transporter-based drug-drug interactions.is a novel 5-nitroimidazole antimicrobial agent indicated for the treatment of infections caused by amoeba, Trichomonas vaginalis, and anaerobic bacteria. 5-Nitroimidazole antimicrobial drugs act via nitroreduction of the molecules in the pathogens (1). As an analog of metronidazole, morinidazole appears to show greater antiparasitic potency against T. vaginalis and amoebic protozoa, but it exhibited relatively weaker toxicity in vitro and in preclinical animal studies compared with metronidazole (2).Following intravenous administration, morinidazole was reported to undergo extensive metabolism in healthy humans, principally via N ϩ -glucuronidation (yielding the N ϩ -glucuronide of S-morinidazole [M8-1] and N ϩ -glucuronide of R-morinidazole [M8-2]) and O-sulfation (yielding the sulfate conjugate of morinidazole [M7]) ( Fig. 1) (3). Renal elimination of morinidazole and its main metabolites accounted for about 71% of a 500-mg dose over 0 to 36 h (3). The primary components in urine were M8-2 (28.4% of the dose), followed by morinidazole (21.2%), M8-1 (6.6%), and M7 (13.0%) (unpublished data). Because of the significant role of the kidney in elimination of morinidazole and its metabolites, it ...

Effects of Rifampin and Ketoconazole on Pharmacokinetics of Morinidazole in Healthy Chinese Subjects

“…Morinidazole as a racemate is regio-and stereoselectively metabolized to R-form and S-form N ϩ -glucuronides and is detectable in plasma and urine. After intravenous infusion of 500 mg of morinidazole to healthy volunteers, approximately 70% of the dose was recovered in urine, of which there was 21.2% parent drug, 28.4% Rform N ϩ -glucuronide, 6.6% S-form N ϩ -glucuronide, and 13% sulfate conjugate. In the renally impaired patients, the AUCs of N ϩ -glucuronide and the sulfate conjugate were dramatically augmented and their renal clearance was reduced by more than 85%.…”

“…In the renally impaired patients, the AUCs of N ϩ -glucuronide and the sulfate conjugate were dramatically augmented and their renal clearance was reduced by more than 85%. Impaired function of renal transporters OAT1 and OAT3 in the patients with renal impairment is responsible for significant changes in the pharmacokinetic behaviors of morinidazole and conjugated metabolites (6).…”

Effects of Tenofovir on the Single-Dose Pharmacokinetics of Intravenous Morinidazole in Healthy Chinese Subjects

“…The potential DDI risk of tenofovir on morinidazole major metabolites was also evaluated based on FDA guidelines (10). Consistent with previous studies, morinidazole was found to be the major circulating drug-related component, whereas the systemic exposures of M8-2, M7, and M8-1 were approximately 14.4%, 1.8%, and 4.0% of the parent drug, respectively (4,11). The metabolic ratio of M2 (C 9 H 16 N 4 O 4 , the loss of C 2 H 2 from morinidazole) in plasma and urine was similar in each group (Fig.…”

“…It has been reported that morinidazole undergoes extensive metabolism, primarily via N-glucuronidation (yielding the N-glucuronide of S-morinidazole [M8-1] and of R-morinidazole [M8-2]) and o-sulfation (yielding the sulfate conjugate of morinidazole [M7]) (3). Morinidazole and its conjugates (M7, M8-1, and M8-2) are mainly excreted through urine (4). The main transporters involved in the renal secretion of drugs in humans include organic anion transporter (OAT) 1, OAT 3, and organic cation transporter (OCT) 2 (5)(6)(7).…”

Challenges and Opportunities with Predicting In Vivo Phase II Metabolism via Glucuronidation From In Vitro Data

“…A recent study showed that daidzein-7-glucuronide was also transported by OATP2B1 (84). In OAT1/3 or OCT2 transfected HEK cells, OAT3 was identified as the only transporter mediating the uptake of morinidazole glucuronide (85). The glucuronide metabolite of sorafenib was also identified as a substrate of OATP1B1, Oatp1b2, and OATP1B3 in transfected HEK cells (86).…”