Evaluation of hydroxyimine as cytochrome P450-selective prodrug structure.
Hydroxyimine derivatives of ketoprofen (1) and nabumetone (2) were synthesized and evaluated in vitro and in vivo as cytochrome P450-selective intermediate prodrug structures of ketones. 2 released nabumetone in vitro in the presence of isolated rat and human liver microsomes and in different recombinant human CYP isoforms. Bioconversion of 2 to both nabumetone and its active metabolite, 6-methoxy-2-naphthylacetic acid (6-MNA), was further confirmed in rats in vivo. Results indicate that hydroxyimine is a useful intermediate prodrug structure for ketone drugs.
Kumpulainen
Hanna
H
Department of Pharmaceutical Chemistry, University of Kuopio, PO Box 1627, FI-70211 Kuopio, Finland.
Mähönen
Niina
N
Laitinen
Marja-Leena
ML
Jaurakkajärvi
Marja
M
Raunio
Hannu
H
Juvonen
Risto O
RO
Vepsäläinen
Jouko
J
Järvinen
Tomi
T
Rautio
Jarkko
J
D000410:Alanine Transaminase / Q000032:analysis; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry* / Q000493:pharmacokinetics; D002021:Buffers; D002074:Butanones / Q000737:chemistry / Q000378:metabolism; D002097:C-Reactive Protein / Q000032:analysis; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry / Q000378:metabolism*; D004355:Drug Stability; D006801:Humans; D006868:Hydrolysis; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000737:chemistry / Q000378:metabolism; D007660:Ketoprofen / Q000737:chemistry / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D000077430:Nabumetone; D009280:Naphthaleneacetic Acids / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis; D020030:Nitric Oxide Donors / Q000737:chemistry* / Q000493:pharmacokinetics; D010091:Oximes / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar; D044967:Serum; D012995:Solubility
D000894:Anti-Inflammatory Agents, Non-Steroidal; D002021:Buffers; D002074:Butanones; D007527:Isoenzymes; D009280:Naphthaleneacetic Acids; D020030:Nitric Oxide Donors; D010091:Oximes; D011355:Prodrugs; D009569:Nitric Oxide; D002097:C-Reactive Protein; D003577:Cytochrome P-450 Enzyme System; D007660:Ketoprofen; C044612:6-methoxy-2-naphthylacetic acid; D000410:Alanine Transaminase; D000077430:Nabumetone