Studies on the metabolic fate of M17055, a novel diuretic (6). Assessment for drug-drug interactions of M17055 in metabolism, distribution and excretion.
1. The potential of M17055, a novel diuretic candidate, to affect the activities of human CYP enzymes, alter the plasma unbound fraction and compete with concomitant drugs in renal secretion as part of an assessment for drug-drug interactions in metabolism, distribution and excretion was investigated. 2. The effects of M17055 on the activities of human CYP1A2, CYP2E1, CYP2C9, CYP2C19, CYP2D6 and CYP3A4 were considered negligible at clinically relevant concentrations. 3. The majority of M17055 (99%) was bound to human plasma proteins, but it is unlikely to alter the binding of other clinically relevant drugs. 4. The renal clearance of M17055 (corrected for the plasma unbound fraction in male rats) substantially exceeded the glomerular filtration rate and was markedly reduced by treatment with probenecid, suggesting that the renal excretion of M17055 is controlled predominantly by an active secretion mechanism. 5. The results show that M17055 is unlikely to cause or undergo significant pharmacokinetic interactions with concomitant drugs in metabolism and distribution. However, when it is administered simultaneously with certain organic anions, drug-drug interactions during kidney excretion may be possible.
Nakajima
H
H
Drug Metabolism and Pharmacokinetics Laboratory, Research Center, Mochida Pharmaceutical Co., Ltd, 722 Jimba-aza-Uenohara, Gotemba Shizuoka 412-8524, Japan. h-naka@mochida.co.jp
Nakanishi
T
T
Naba
H
H
Nakai
K
K
Matsumoto
S
S
Nagasawa
K
K
Ida
K
K
Ogihara
T
T
Ohzawa
N
N
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D065731:Cytochrome P-450 CYP2C19; D065729:Cytochrome P-450 CYP2C9; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004232:Diuretics / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006801:Humans; D008297:Male; D006899:Mixed Function Oxygenases / Q000378:metabolism; D008956:Models, Chemical; D010091:Oximes / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D011485:Protein Binding; D015363:Quinolones / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D051381:Rats; D017208:Rats, Wistar
D004232:Diuretics; D010091:Oximes; D015363:Quinolones; C079648:7-chloro-2,3-dihydro-1-(2-methylbenzoyl)-4(1H)-quinolinone 4-oxime-O-sulfonic acid; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D019392:Cytochrome P-450 CYP2E1; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; C104464:CYP3A protein, human; D019388:Cytochrome P-450 CYP1A2; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human