THE EFFECT OF TOLERANCE AND WITHDRAWAL ON THE IN VIVO METABOLISM OF N-C¹⁴-METHYL-DIHYDRO-MORPHINE IN THE RAT

¹ Department of Pharmacology, College of Medicine, The University of Iowa, Iowa City, Iowa

N-C¹⁴-methyl-dihydromorphine (C¹⁴-DHM) was synthesized by catalytic hydrogenation of normorphine and methylation of dihydronormorphine with C¹⁴-para-formaldehyde. Twenty-four hours after s.c. injection of 2 mg/kg of (C¹⁴-DHM, the percent recovery as expired C¹⁴O₂ in nontolerant female and male rats was 0.5 and 3.7%, respectively. Male rats were injected s.c. twice daily, initially at a dosage of 10 mg/kg, which was increased by 5 mg/kg/week for seven weeks to a final dosage of 45 mg/kg. By the end of the first week, these chronically treated rats showed a decrease of expired C¹⁴0₂ from the initial control level of 3.7% of the injected radioactivity to 0.8% and by three weeks to a minimum of 0.5%. Male rats given DHM for 49 days, then abruptly withdrawn from the drug, required nine days for respiratory C¹⁴O₂, to return to nontolerant levels, whereas animals given DHM for four days required four days to restore the N-demethylating activity. During the first 24 hours after injection, the urinary excretion of the drug by nontolerant male rats was 23.1% as free DHM and 18.1% as conjugated DHM; by female rats, 27.4% and 302%, respectively. The fecal excretion of the drug by both male and female rats was 25% as free dihydromoruhine.