Relation of plasma morphine concentrations to severity of abrupt withdrawal in morphine-dependent monkeys.

Plasma morphine levels were measured during abrupt withdrawal in four chronically dependent female monkeys. Approximately 12 hr after withdrawal, the morphine plasma concentrations were about 8 to 10 ng/ml, at which time all of the animals showed mild to moderate symptoms of opiate withdrawal. Severity of withdrawal showed a negative correlation (r = -0.93, P less than .001) with the falling phase of plasma morphine. It may be concluded that, under the conditions of this experiment, significant morphine withdrawal symptoms arose despite measurable plasma concentrations of morphine and that the relationship between plasma concentrations and withdrawal may be quantified according to a linear pharmacokinetic model for a given chronic dose (3.0 mg/kg q 6 hr) of morphine.

Pharmacokinetics and analgesic effect of pethidine (meperidine) and its metabolites in the rat.

The pharmacokinetics of pethidine (meperidine) and norpethidine (normeperidine) have been investigated after iv administration of pethidine in the rat. The plasma concentration-time curve for pethidine could be described by a triexponential function. The calculated half-lives were 6.0, 18.5, and 64.5 min. Norpethidine, metabolically formed from pethidine, reached maximum plasma concentrations after 30 min and declined biexponentially with half-lives of 66.8 and 301 min. The time course of analgesia after iv administration of pethidine, norpethidine, and p-hydroxypethidine has also been evaluated. When the pharmacokinetic data were compared with the time course of analgesia, the plasma levels of pethidine could be correlated with the analgesic effect after the first rapid distribution phase. The pharmacokinetic constants for pethidine and norpethidine were used to stimulate the plasma levels of these compounds after multiple doses of pethidine. Accumulation of norpethidine was demonstrated to occur, which may be of importance when toxic and analgesic effects of pethidine are evaluated.

Pharmacokinetic interpretation of the enterohepatic recirculation and first-pass elimination of morphine in the rat.

Morphine was administered to rats by oral, intraportal, and intravenous routes in a dose of 7.6 mg . kg-1. From the serum concentration data after intraportal administration it was calculated that the first-pass elimination of morphine in the liver amounts to 72 +/- 2% (SD). The first-pass fraction eliminated after oral administration was 85 +/- 7% (SD), thus yielding a contribution by the gut mucosa of 46% to the overall first-pass elimination after an oral dose. The results were obtained with a general compartmental model which included the kinetics of enterohepatic recirculation. The oral availability was also estimated with the aid of pharmacological effect data. This availability was in good agreement with the corresponding value determined from the serum concentration data. The results suggest that morphine is subjected to enterohepatic recirculation and that the slowest phase of decline of morphine concentrations in serum might be due to this physiological process.