morinidazole and Renal-Insufficiency

To evaluate the pharmacokinetics of morinidazole in individuals with severe renal impairment (RI).. This open-label Phase I study enrolled healthy volunteers and patients with severe RI aged 18 - 65 years. All subjects received a single infusion of sodium chloride injection with 500 mg morinidazole. Plasma and urine concentration of morinidazole and one of its metabolites (M4-1) were evaluated by using HPLC-UV and HPLC-MS/MS respectively. Pharmacokinetic parameters were calculated by Phoenix WinNonlin 6.0 software.. 22 individuals (healthy: n = 11, severe RI: n = 11) received morinidazole. In both groups, maximum plasma concentration of morinidazole was reached within 1 hour, while the tmax of M4-1 differed greatly. Both AUC0-t and AUC0-∞ of morinidazole were 1.4 times higher in patients with severe RI, while M4-1 were over 7 times higher than healthy groups. Renal excretion of unchanged morinidazole was decreased by 65% in patients with RI, and M4-1 was decreased by 72%. Apparent correlation between CLcr and CL, AUC, t1/2 and CLr were seen in two groups.. A single dose of 500 mg morinidazole is well tolerated. Changes in pharmacokinetic parameters of morinidazole and M4-1 are seen in patients with RI and may be clinically important.

Topics: Adolescent; Adult; Anti-Infective Agents; Area Under Curve; Female; Humans; Kidney; Male; Middle Aged; Nitroimidazoles; Renal Insufficiency; Young Adult

A novel simple bioanalytical method of high performance liquid chromatography (HPLC) for simultaneous quantification of morinidazole and its carbonylation metabolite (M1) in human plasma was developed and validated. The calibration curves for morinidazole and M1 were linear over concentration ranges of 23.99-1.464×10(4)μgL(-1) and 5.407-3300μgL(-1), respectively. Intra- and inter-day precision and accuracy results satisfied the acceptable criteria for bioanalytical method validation. This method could be a useful method for clinical pharmacokinetic studies of morinidazole and its carbonylation metabolite, and it has been applied to a pharmacokinetic study involving 11 renal insufficiency patients and 11 healthy volunteers.

Topics: Adult; Anti-Bacterial Agents; Calibration; Case-Control Studies; Chromatography, High Pressure Liquid; Humans; Middle Aged; Nitroimidazoles; Renal Insufficiency; Reproducibility of Results

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 (Km = 28.6 and 54.0 μM, 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.

Topics: Adult; Anti-Bacterial Agents; Area Under Curve; Cell Line; Cimetidine; Female; HEK293 Cells; Humans; Infusions, Intravenous; Kidney; Male; Middle Aged; Nitroimidazoles; Organic Anion Transport Protein 1; Organic Anion Transporters, Sodium-Independent; Probenecid; Protein Binding; Renal Insufficiency; Transfection; Young Adult

Morinidazole is a new third-generation 5-nitroimidazole antimicrobial drug. To investigate the pharmacokinetic profiles of morinidazole and its major metabolites in humans, a liquid chromatography-tandem mass spectrometry method was developed and validated for simultaneous determination of morinidazole, its N-oxide metabolite (M4-1), a sulfate conjugate (M7), and two diastereoisomeric N(+)-glucuronides (M8-1 and M8-2) in human plasma. A simple acetonitrile-induced protein precipitation was employed to extract five analytes and internal standard metronidazole from 50μL human plasma. To avoid the interference from the in-source dissociation of the sulfate and achieve the baseline-separation of diastereoisomeric N(+)-glucuronides, all the analytes were separated from each other with the mobile phase consisting of 10mM ammonium formate and acetonitrile using gradient elution on a Hydro-RP C(18) column (50mm×2mm, 4μm) with a total run time of 5min. The API 4000 triple quadrupole mass spectrometer was operated under the multiple reaction-monitoring mode using the electrospray ionization technique. The developed method was linear in the concentration ranges of 10.0-12,000ng/mL for morinidazole, 1.00-200ng/mL for M4-1, 2.50-500ng/mL for M7, 3.00-600ng/mL for M8-1, and 10.0-3000ng/mL for M8-2. The intra- and inter-day precisions for each analyte met the accepted value. Results of the stability of morinidazole and its metabolites in human plasma were also presented. The method was successfully applied to the clinical pharmacokinetic studies of morinidazole injection in healthy subjects, patients with moderate hepatic insufficiency, and patients with severe renal insufficiency, respectively.

Topics: Chromatography, High Pressure Liquid; Drug Stability; Glucuronides; Humans; Least-Squares Analysis; Nitroimidazoles; Oxides; Renal Insufficiency; Reproducibility of Results; Sulfates; Tandem Mass Spectrometry