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the spectrum of 11; mass spectrum (70 eV, glpc inlet, ion source 230') ( Figure 6).Jones Oxidation of .-Jones reagent14 (8 N , 0.85 ml) was added dropwise to a solution of 1.125 g (2.92 mmol) of alcohol 4 in 100 ml of acetone a t 20'. The solution was warmed to room temperature and then diluted with an equal volume of water. The ether extract of this solution was washed with water (twice), saturated sodium bicarbonate solution, and brine. Evaporation of the solvent and crystallization from acetone ave0.9 g (81%) of pure cholest-5-en-4-one6: mp 111-112'; /.r (6 AZFo 241 m M (e 6000) [lit.I5 mp 111-112'; A~~o f " 241 m 7200)l; Y: : : "1675 and 1620 cm-l. Reaction of Sodium Hydride with 3p-p-Toluenesulfonoxycholest-5-en+-01 (I).--To a stirred solution of 500 mg (0.9 mmol) of tosylate 1 in 25 ml of tetrahydrofuran (thf) under a nitrogen atmosphere was added 41.0 g (0.9 mmol) of sodium hydride on mineral oil 52.8% NaH). The mixture waa heated at reflux for 3 hr, cooled, and 1 equiv of water was added dropwise. The resulting solution was filtered and evaporated to dryness a t reduced pressure. The brown residue which resulted was dissolved in ether and the ether solution was washed with water (twice), 5% sodium bicarbonate, and brine, and then dried over sodium sulfate. Evaporation of the solvent gave 0.45 g of crude %

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1. Following a subcutaneous dose (4mg/kg) of [3H]methadone, peak levels of drug occurred in plasma, tissues and selected areas of the central nervous system (CNS) 2h after injection in both non-tolerant and tolerant dogs. Highest concentrations of methadone were attained in bile and lung compared to other tissues. 2. Levels of methadone in plasma, tissue and CNS of tolerant and non-tolerant animals were not markedly different up to 8h after injection, but a much faster rate of egression of free drug (lower t1/2) was observed subsequently in tolerant dogs. 3. Peak levels of methadone in various areas of the CNS ranged between 2-7 (spinal cord) to 3-6 (thalamus) mug/g in non-tolerant and 3-0 -rebellum) to 4-1 (thalamus) mug/g in tolerant dogs 2h after injection. No marked accumulation of methadone occurred in selected areas of the CNS in spite of the persistence of drug in these areas. 4. The plasma protein electrophoretic profiles did not differ between control, non-tolerant and tolerant dogs. 5. Similar qualitative patterns of metabolites were observed in non-tolerant and tolerant dogs and the development of tolerance did not appear to modify the metabolic pathways of methadone.