Metabolism of the analgesic drug, tramadol hydrochloride, in rat and dog.
1. Metabolism of the analgesic agent, tramadol hydrochloride, was investigated after a single oral administration of 14C-tramadol to four rats (50)mgkg(-1) and two dogs (20)mg kg(-1). 2. Recovery of total radioactivity in rat and dog urine samples over 24 h was 73 and 65% of the radioactive dose, respectively. 3. Unchanged tramadol and a total of 24 metabolites, consisting of 16 Phase I metabolites and eight conjugates (seven glucuromides, one sulphate), were isolated and tentatively identified, which accounted for > 52% of the dose in urine of both species. 4. Of the metabolites, five (M1-5) were previously identified. 5. The metabolites were formed via the following six metabolic pathways: O-demethylation, N-demethylation, cyclohexyl oxidation, oxidative N-dealkylation, dehydration and conjugation. 6. Pathways 1-3 appear to be major steps, forming seven O-desmethyl/N-desmethyl and hydroxy-cyclohexyl metabolites in major quantities. 7. Pathways 1-3 in conjunction with pathway 6 produced four glucuronides along with four minor conjugates. 8. In addition, the in vitro metabolism of tramadol was conducted using rat hepatic S9 fraction in the presence of an NADPH-generating system. Unchanged tramadol (30% of the sample) plus nine metabolites, M1-7, tramadol-N-oxide (M31) and OH-cyclohexyl-M1 (M32), were profiled and tentatively identified based on MS and MS/MS data.
Wu
W N
WN
Division of Preclinical Development, The R.W. Johnson Pharmaceutical Research Institute, Spring House, PA 19477, USA.
McKown
L A
LA
Gauthier
A D
AD
Jones
W J
WJ
Raffa
R B
RB
D000701:Analgesics, Opioid / Q000493:pharmacokinetics* / Q000652:urine; D000818:Animals; D002855:Chromatography, Thin Layer; D004285:Dogs; D005260:Female; D020719:Glucuronides / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D008956:Models, Chemical; D051381:Rats; D017208:Rats, Wistar; D013045:Species Specificity; D013997:Time Factors; D014147:Tramadol / Q000493:pharmacokinetics* / Q000652:urine
D000701:Analgesics, Opioid; D020719:Glucuronides; D014147:Tramadol