title: Pharmacokinetics and O-dealkylation of morphine-3-alkyl ethers in the rat. A radioimmunoassay study.
abstract: Radioimmunoassay procedures were used to investigate the relationship between the chemical structure and disposition of morphine, codeine, ethylmorphine, t-butylmorphine, and pholcodine. Male Sprague-Dawley rats received po or iv doses of each drug equivalent to 10 mg/kg free base. Blood samples were collected at various times over the 6-hr period after each drug administration, and plasma concentrations of the parent drugs and metabolically produced morphine were determined. A single ethylmorphine antiserum was used for analysis of codeine, ethylmorphine, t-butylmorphine, and pholcodine in separate experiments, whereas a specific morphine antiserum was used in the radioimmunoassay of this compound. The absolute oral bioavailabilities of morphine, codeine, ethylmorphine, and t-butylmorphine all were below 10%, whereas that of pholcodine was over 40%. Terminal half-lives of morphine, codeine, ethylmorphine, and t-butylmorphine after iv administration all were less than 45 min, while that of pholcoline was over 2 hr. Codeine, ethylmorphine, t-butylmorphine, and pholcodine did not appear to undergo conjugation, as evidenced by the similarity between areas under the curve for total (unconjugated plus conjugated) and parent (unconjugated) drugs. Amounts of metabolically produced morphine in rats treated with codeine, ethylmorphine, t-butylmorphine, or pholcodine differed markedly. After oral administration, presystemic O-dealkylation of codeine and ethylmorphine was much greater than that of t-butylmorphine or pholcodine, presumably due to the presence of much bulkier 3-alkyl substituents in the latter compounds. Thus, the ratio of the morphine AUC to that of parent drug after po administration was 1.37 for codeine and 1.60 for ethylmorphine, but only 0.08 for t-butylmorphine and 0.01 for pholcodine.(ABSTRACT TRUNCATED AT 250 WORDS)
mesh_terms: D000818:Animals; D003061:Codeine / Q000031:analogs & derivatives / Q000378:metabolism; D003429:Cross Reactions; D003640:Dealkylation; D005036:Ethylmorphine / Q000378:metabolism; D006234:Handling, Psychological; D007700:Kinetics; D008297:Male; D009020:Morphine / Q000378:metabolism; D009022:Morphine Derivatives / Q000378:metabolism; D009025:Morpholines / Q000378:metabolism; D011863:Radioimmunoassay; D051381:Rats; D011919:Rats, Inbred Strains; D013997:Time Factors
chemical_list: D009022:Morphine Derivatives; D009025:Morpholines; C036160:3-O-tert-butylmorphine; D009020:Morphine; C008872:pholcodine; D005036:Ethylmorphine; D003061:Codeine