| Abstract: | The pharmacokinetics of the synthetic narcotic agent LAAM, its pharmacologically active, demethylated metabolites NORLAAM and DINORLAAM, and also the dextro-enantiomer DAAM, were examined following intravenous doses of all four compounds, and oral doses of LAAM and DAAM to dogs. Extensive tissue uptake of all compounds occurred following intravenous doses. NORLAAM penetrated into tissues to a greater extent than LAAM or DINORLAAM and also exhibited the longest biological half-life (11·7 h) in plasma compared to LAAM (6·5 h) and DINORLAAM (3·6 h). The elimination rate of DINORLAAM was prolonged following oral doses of LAAM and intravenous doses of NORLAAM, and it is suggested that prolonged pharmacologic activity of LAAM may be associated with rate-limiting demethylation of NORLAAM. DAAM was taken up exrensively by tissues but to a smaller extent than LAAM. Following oral doses, the bioavailability of LAAM as unchanged drug was 22·6 and 32·5 per cent in two dogs while that of DAAM was 4·9, 9·3, and 14·6 per cent in three dogs. Poor bioavailability of unchanged drug from oral doses appears to be due partly to first-pass metabolism and is partially compensated for by increased plasma levels of pharmacologically active metabolites. Extensive tissue uptake of LAAM and its active metabolites, and their long plasma half-lives, may be partially responsible for the prolonged pharmacologic activity of LAAM reported in patients maintained on this drug. |
