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ABSTRACT:Morinidazole [R,S-1-(2-methyl-5-nitro-1H-imidazol-1-yl)-3-morpholinopropan-2-ol] is a new 5-nitroimidazole class antimicrobial agent. The present study aimed to determine the metabolism and pharmacokinetics of morinidazole in humans and to identify the enzymes responsible for the formation of the major metabolites. Plasma and urine samples were collected before and after an intravenous drip infusion of 500 mg of racemic morinidazole. Ultraperformance liquid chromatography/quadrupole time-of-flight mass spectrometry revealed 10 metabolites. Morinidazole glucuronidation, followed by renal excretion, was the major elimination pathway, accounting for 35% of the dose. The metabolic pathway displayed regioselectivities and stereoselectivities. Unexpectedly, the nitrogen atom of the morpholine ring, rather than the aliphatic hydroxyl group at the side chain, was glucuronidated to form S-morinidazole glucuronide (M8-1) and R-enantiomer glucuronide (M8-2). The plasma exposure of M8-2 was 6-fold higher than that of M8-1, accounting for 22.9 and 3.96% of the parent drug exposure, respectively. Investigation of morinidazole glucuronidation using human liver microsomes (HLMs) and 12 recombinant UDP glucuronosyltransferases (UGTs) indicated that this biotransformation was mainly catalyzed by UGT1A9. A kinetic study showed that N

Emerging evidence indicates an important role for the breast cancer resistance protein (BCRP) in limiting brain penetration of substrate drugs. While in vitro transwell assays can provide an indication of BCRP substrate potential, the predictability of these assays in relation to in vivo brain penetration is still under debate. The present study examined the correlation of BCRP membrane protein expression level and transcellular transport activity across Madin-Darby canine kidney (MDCK) II monolayers. We expressed human BCRP or murine BCRP1 in MDCKII wild-type cells using BacMam2 virus transduction. The selective P-glycoprotein (P-gp) inhibitor LY335979 (1 M) was included in the transport medium to measure BCRP-mediated transcellular transport for P-gp and BCRP cosubstrates. The BCRP levels in membrane extracts from MDCKII-BCRP or MDCKII-Bcrp1 cells were quantified by liquid chromatography-tandem mass spectrometry. The results are summarized as follows: 1) the membrane protein expression levels correlate with the corrected efflux ratios of substrates for human BCRP and murine BCRP1 within the efflux ratios investigated; 2) we demonstrate good concordance in rank order between the BCRP and BCRP1-mediated efflux ratios for 12 drugs; and 3) we propose an approach to contextualize in vitro BCRP transport data of discovery compounds by comparing them to the in vitro and in vivo transport data of the reference drug dantrolene and taking into account interbatch variation in BCRP expression. This approach correctly predicted compromised brain penetration for 25 discovery compounds in rodents, which were BCRP substrates but not P-gp or weak P-gp substrates. These results suggest that BCRP-expressing MDCKII cells are useful in predicting the in vivo role of BCRP in brain penetration.

Morinidazole, a 5-nitroimidazole antimicrobial drug, has been approved for the treatment of amoebiasis, trichomoniasis, and anaerobic bacterial infections in China. It was reported that drug-drug interaction happened after the coadministration of ornidazole, an analog of morinidazole, and rifampin or ketoconazole. Therefore, we measured the plasma pharmacokinetics (PK) of morinidazole and its metabolites in the healthy Chinese volunteers prior to and following the administration of rifampin or ketoconazole using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The area under the concentration-time curve from time 0 to time t (AUC 0-t ) and maximum concentration in serum (C max ) of morinidazole were decreased by 28% and 23%, respectively, after 6 days of exposure to 600 mg of rifampin once daily; the C max s of N ؉ -glucuronides were increased by 14%, while their AUC 0-t s were hardly changed. After 7 days of exposure to 200 mg of ketoconazole once daily, the AUC 0-t and C max of the parent drug were not affected significantly. C max s of N ؉ -glucuronides were decreased by 23%; AUC 0-t s were decreased by 14%. The exposure of sulfate conjugate was hardly changed after the coadministration of rifampin or ketoconazole. Using recombinant enzyme of UGT1A9 and human hepatocytes, the mechanism of the altered PK behaviors of morinidazole and its metabolites was investigated. In human hepatocytes, ketoconazole dose dependently inhibited the formation of N ؉ -glucuronides (50% inhibitory concentration [IC 50 ], 1.5 M), while rifampin induced the mRNA level of UGT1A9 by 28% and the activity of UGT1A9 by 53%. In conclusion, the effects of rifampin and ketoconazole on the plasma exposures of morinidazole and N ؉ -glucuronide are less than 50%; therefore, rifampin and ketoconazole have little clinical significance in the pharmacokinetics of morinidazole. Morinidazole is developed as a 5-nitroimidazole antimicrobial injection with potent activities against anaerobic Gram-negative sporeless bacilli and Gram-positive cocci (1). Its efficacy against Clostridium perfringens, Bacteroides fragilis, Veillonella parvula, Bacteroides distasonis, Bacteroides ovatus, Bacteroides vulgatus, and Bacteroides melaninogenicus is equal to that of ornidazole and superior to those of metronidazole and tinidazole. It has been approved for the treatment of amoebiasis, trichomoniasis, and anaerobic bacterial infections in China. However, its antibacterial spectrum is still limited; thus, there is the possibility of concomitant administration with other antibacterial agents in the treatment of mixed infections. It was reported that drug-drug interaction (DDI) happened after the coadministration of ornidazole, an analog of morinidazole, with rifampin or ketoconazole. The pharmacokinetic parameters of ornidazole in healthy volunteers-area under the curve (AUC), peak concentration (C max ), elimination half-life (t 1/2 ), and clearance (CL)-were decreased by 21.16%, 20.43%, 18.11%, and 32.14%, respectively, by rifampin. The altered pharmacok...