The biologic disposition of methadone in acute and during chronic administration was studied in 12 human volunteers. In the acute study a biexponential methadone plasma level decay was observed. The acute primary half-life (t1/2) of 14.3 hr in combination with the acute secondary t1/2 of 54.8 hr were longer than the single exponential chronic t1/2 of 22.2 hr determined in the same subjects. The urinary and fecal excretion of methadone and its mono-N-demethylated metabolite increased from 22.2% in the acute to 62.0% in the chronic phase of the study. The urinary metabolite 1 to methadone ratio tripled from the acute to the chronic phase. The pupillary effects of methadone monitored throughout 24 hr were nearly the same in magnitude in the acute and the chronic studies, whereas the plasma levels increased 3- to 8-fold following chronic methadone administration. These findings suggest that both dispositional and pharmacologic tolerance are involved in the development of tolerance following chronic administration of methadone.

The time course of methadone in the plasma of 5 methadone maintenance sub;ects receiving a single daily oral dose of 100 or 120 mg. has been determined. The predose mean plasma level of methadone was 0.48 fig per milliliter. The peak plasma level occurred at 4 hours with an average value of 0.86 fig per milliliter. This level slowly declined so that 24 hours after administration the mean plasma level had reached a value (0.46 fig per milliliter) approximately equal to the predose level. The mean apparent half-life of methadone in these sub;ects was 25 hours. Data on the renal clearance of methadone indicate that the drug is partially reabsorbed by the kidney and that this reabsorption is pH dependent.

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Department of Pharmacology, Cornell University Medical CollegeThe disposition of propoxyphene in man has been only reeently explored beeause earlier methods were either nonspecifie or laeked the sensitivity required to quantitate the sm all amounts of this drug present in human plasma. In 1968, Wolen and Gruber l l developed a gas-liquid chromatographie ( GLC ) method for the quantitative determination of propoxyphene in plasma. They found that 3 subjeets who had reeeived the same dose differed widely in plasma propoxyphene levels. This' variation was unrelated to the body weight of the subjects. MeMahon and associates" studied propoxyphene disposition in man with 14C-Iabeled drug. They found that N-demethylation was an important biotransformation pathway for propoxyphene, and in man norpropoxyphene was the most important biotransformation produet. 302In order to determine more precisely the degree of individual variation in the disposition of propoxyphene, a GLC method was developed that permits the simultaneous quantitation of both propoxyphene

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