Metabolism and disposition of 4-(methylnitrosamino)-1-(3-pyridyl)-1- butanone (NNK) in rhesus monkeys.
Metabolism and disposition of the tobacco-specific N-nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a potent rodent lung carcinogen, were studied in rhesus monkeys. In three males receiving a single i.v. dose of [5-3H]NNK (0.72 mCi; 4.6-9.8 microg/kg), urine was collected for 10 days. Within the first 24 h, 86.0 +/- 0.7% of the dose was excreted. NNK-derived radioactivity was still detectable in urine 10 days after dosing (total excretion, 92.7 +/- 0.7%). Decay of urinary radioactivity was biexponential with half-lives of 1.7 and 42 h. Metabolite patterns in urine from the first 6 h closely resembled those reported previously for patas monkeys; end products of metabolic NNK activation represented more than 50% of total radioactivity. At later time points, the pattern shifted in favor of NNK detoxification products (60-70% of total radioactivity in urine), mainly 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and its O-glucuronide conjugates. One female rhesus monkey received a single i.v. dose of [5-3H]NNK (1.72 mCi; 28.4 microg/kg) under isoflurane anesthesia; biliary excretion over 6 h (0.6% of the dose) was 10 times less than predicted by our previously reported rat model. No preferential excretion of NNAL glucuronide was observed in monkey bile. Collectively, these results suggest that the rhesus monkey could be a useful model for NNK metabolism and disposition in humans.
Meger
M
M
Walther Straub-Institut für Pharmakologie und Toxikologie, Ludwig-Maximilians-Universität München, Munich, Germany.
Richter
E
E
Zwickenpflug
W
W
Oehlmann
C
C
Hargaden
M B
MB
A-Rahim
Y I
YI
Vesell
E S
ES
D000818:Animals; D001646:Bile / Q000378:metabolism; D001659:Biliary Tract / Q000378:metabolism; D002273:Carcinogens / Q000378:metabolism / Q000493:pharmacokinetics; D005260:Female; D005750:Gastric Juice / Q000378:metabolism; D007275:Injections, Intravenous; D007668:Kidney / Q000378:metabolism; D007700:Kinetics; D008253:Macaca mulatta; D008297:Male; D009602:Nitrosamines / Q000378:metabolism* / Q000493:pharmacokinetics* / Q000652:urine; D014018:Tissue Distribution
D002273:Carcinogens; D009602:Nitrosamines; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone