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 clinical structure and disposition of morphine [M] codeine [C], ethylmorphine [EM], tert-butylmorphine [TBM] and pholcodine [PC]. Male Sprague-Dawley rats received p.o. or i.v. doses of each drug equivalent to 10 mg/kg free base. Blood samples were collected at various times over the 6-h period after each drug administration, and plasma concentrations of the parent drugs and metabolically produced M were determined. A single EM antiserum was used for analysis of C, EM, TBM and PC in separate experiments, while a specific M antiserum was used in the radioimmunoassay of this compound. The absolute oral bioavailabilities of M, C, EM and TBM all were 10%, while that of PC was > 40%. Terminal half-lives of M, C, EM and TBM after i.v.-administration all were < 45 min, while that of PC was > 2 h. C, EM, TBM and PC did not appear to undergo conjugation, as evidenced by the similarity between areas under the curve [AUC] for total (unconjugated plus conjugated) and parent (unconjugated) drugs. Amounts of metabolically produced M in rats treated with C, EM, TBM or PC differed markedly. After oral administration, presystemic O-dealkylation of C and EM was much greater than that of TBM or PC, presumably due to the presence of much bulkier 3-alkyl substituents in the latter compounds. The ratio of the M AUC to that of parent drug after p.o. administration was 1.37 for C and 1.60 for EM, but only 0.08 for TBM and 0.01 for PC. Total M AUC were 3- to 24-fold higher than those of unconjugated M after the administration of each drug. The poor O-dealkylation of TBM and PC may contribute to their reported lack of analgesic activity and to the low addiction potential reported for the latter compound.