Garrett_1980_J.Pharm.Sci_69_1116

The pharmacokinetics of intravenously administered heroin and its derived metabolites, 6-O-monoacetylmorphine, morphine, and the glucuronidated conjugates of morphine, were studied in dogs at doses of 0.1-0.5 mg/kg. The spontaneous hydrolysis of the sampled biological fluids was inhibited by tetraethyl pyrophosphate so that the heroin concentration at the times of sampling could be analyzed for the first time. Heroin is concomitantly rapidly metabolized and distributed among body tissues. Metabolic clearance of 2916 +/- 321 ml/min are largely extrahepatic and are sixfold greater than hepatic blood flow. Nevertheless, the terminal half-life of 60-90 min resembles that of morphine and is maintained by the rate-determining return of distributed heroin from esterase-free tissues. Normal renal clearances of 43 +/- 6 ml/min result in 1.6 +/- 0.2% of the dose being renally excreted unchanged. The large overall volume of distribution, 344 +/- 60 liters, is indicative of heroin's wide distribution and lipophilicity, which rapidly equilibrates heroin in the plasma with the cerebrospinal fluid. Heroin is concomitantly metabolized almost equally to 6-O-monoacetylmorphine and morphine. The monoacetylmorphine is metabolized concomitantly to morphine and glucuronide conjugates in a 4:3 ratio and exercises its own activity. Its time course is close to that of heroin, although the total clearance (2200 ml/min) and overall volumes of distribution (90-170 liters) were less. The integrated model of transformations and eliminations was constructed with concomitant metabolism of the heroin metabolite, 6-O-monoacetylmorphine, to morphine and glucuronide conjugates. The assumption that the glucuronide conjugates partition into the bile and systemic circulation in the same ratio as does the conjugate of the derived morphine metabolite gave pharmacokinetic parameters consistent with the morphine pharmacokinetics studied previously and provided excellent fits of the plasma level-time curves of all of the derived metabolites of heroin.