Increased Plasma Exposures of Conjugated Metabolites of Morinidazole in Renal Failure Patients: A Critical Role of Uremic Toxins.
Morinidazole is a 5-nitroimidazole drug. Its sulfate conjugate M7 was a sensitive substrate of organic anion transporter 1 (OAT1) and OAT3, whereasN+-glucuronides M8-1 and M8-2 were only OAT3 substrates. In chronic renal failure (CRF) patients, plasma exposures of the three conjugates increased by 15-fold, which were also found in 5/6 nephrectomized (5/6 Nx) rats in this study. Although the transcriptions of Oat1 and Oat3 in 5/6 Nx rat kidneys decreased by 50%, no difference was observed on the three conjugate uptakes between control and 5/6 Nx rat kidney slices. Thus, the highly elevated endogenous uremic toxins in 5/6 Nx rats and humans, namely, 3-carboxy-4-methyl-5-propyl-2-furanpropionate (CMPF), hippuric acid (HA), and indoxyl sulfate (IS), were considered as influential factors. In rat kidney slices, the uptake of M7, M8-1, and M8-2 was dose dependently reduced by HA and IS, whose plasma concentrations were elevated 5 times in 5/6 Nx rats. In OAT3-overexpressed cells, the three conjugate uptakes were inhibited by CMPF, HA, and IS with IC50values of 19.2, 87.4, and 222μM (M7); 8.53, 39.4, and 161μM (M8-1); and 6.75, 24.1, and 78.3μM (M8-2), respectively. In OAT1-overexpressed cells, CMPF, HA, and IS showed weak inhibition on M7 uptake with IC50values of 187, 162, and 200μM, correspondingly. Results suggest that the reduced mRNA expression of renal transporters in CRF patients may not influence the activities of these transporters. However, accumulated uremic toxins may inhibit the transporters, particularly OAT3, leading to plasma exposure changes of relevant substrates.
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai (F.K., X.P., K.Z., Z.G., X.L., D.Z., X.C.), and University of Chinese Academy of Sciences, Beijing (F.K., D.Z., X.C.), People's Republic of China.
Fandi
F
Kong
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai (F.K., X.P., K.Z., Z.G., X.L., D.Z., X.C.), and University of Chinese Academy of Sciences, Beijing (F.K., D.Z., X.C.), People's Republic of China.
Xiaoyan
X
Pang
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai (F.K., X.P., K.Z., Z.G., X.L., D.Z., X.C.), and University of Chinese Academy of Sciences, Beijing (F.K., D.Z., X.C.), People's Republic of China.
Kan
K
Zhong
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai (F.K., X.P., K.Z., Z.G., X.L., D.Z., X.C.), and University of Chinese Academy of Sciences, Beijing (F.K., D.Z., X.C.), People's Republic of China.
Zitao
Z
Guo
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai (F.K., X.P., K.Z., Z.G., X.L., D.Z., X.C.), and University of Chinese Academy of Sciences, Beijing (F.K., D.Z., X.C.), People's Republic of China.
Xiuli
X
Li
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai (F.K., X.P., K.Z., Z.G., X.L., D.Z., X.C.), and University of Chinese Academy of Sciences, Beijing (F.K., D.Z., X.C.), People's Republic of China.
Dafang
D
Zhong
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai (F.K., X.P., K.Z., Z.G., X.L., D.Z., X.C.), and University of Chinese Academy of Sciences, Beijing (F.K., D.Z., X.C.), People's Republic of China xychen@simm.ac.cn.
Xiaoyan
X
Chen
D000818:Animals; D001692:Biological Transport / Q000502:physiology; D005663:Furans / Q000378:metabolism; D006626:Hippurates / Q000378:metabolism; D006801:Humans; D007200:Indican / Q000378:metabolism; D007668:Kidney / Q000378:metabolism*; D008297:Male; D009593:Nitroimidazoles / Q000378:metabolism*; D027362:Organic Anion Transport Protein 1 / Q000378:metabolism; D029362:Organic Anion Transporters, Sodium-Independent / Q000378:metabolism; D010949:Plasma / Q000378:metabolism*; D011422:Propionates / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D051437:Renal Insufficiency / Q000097:blood* / Q000378:metabolism*; D014511:Uremia / Q000097:blood / Q000378:metabolism*
D005663:Furans; D006626:Hippurates; D009593:Nitroimidazoles; D027362:Organic Anion Transport Protein 1; D029362:Organic Anion Transporters, Sodium-Independent; D011422:Propionates; C041693:3-carboxy-4-methyl-5-propyl-2-furanpropionic acid; D007200:Indican; C030514:hippuric acid; C547405:morinidazole