Abstract
Meptazinol, dl-m (3 ethylhexahydro-1-methyl-1H-azepin-3-yl) phenol hydrochloride is a new analgesic agent, which from animal studies appears to have a low addiction liability. By contrast however, the desmethyl derivative, although still a potent analgesic was shown to have a much greater addiction potential. Metabolic studies using a novel dual labelling approach showed no evidence for the formation of normeptazinol in animals or man. The major metabolic pathway seen in all the species so far investigated involves rapid conjugation with glucuronic acid. A minor metabolite found only in the urine of monkeys and man has been tentatively identified as 6-ethyl-6-(m hydroxyphenyl)-1-methylhexahydro-azepin-(2H)-2-one This metabolite was shown to be biologically inactive. Pharmacological studies showed meptazinol to be considerably less potent after oral as compared to parenteral administration. A good correlation between the intensity of the drug's biological effects and plasma levels of the compound was demonstrated in rats, mice and monkeys. Oral administration of the drug was shown to produce much lower plasma levels of the free drug than parenteral dosage. This did not appear to be due to incomplete absorption since the drug was efficiently absorbed in all these species. However the rate of absorption was considerably slower in monkeys and man, an effect which was shown to cause more extensive first pass conjugation of the drug in these species. This slower absorption was at least partly due to the longer gastric emptying time in these species. In addition, studies in the monkey showed the drug to have a marked retarding action on stomach emptying, an effect not seen in the rat. Rectal administration of the drug has been shown to provide a means of circumventing the problem of extensive first pass metabolism and effectively increasing the drug's potency. In man plasma levels of the drug resulting from rectal dosage were five to ten times higher than when the same dose was given orally.