Methadone is a clinically used opioid agonist that is oxidatively metabolized by cytochrome P450 (CYP) isoforms to a stable metabolite, EDDP. Methadone is a chiral drug administered as the racemic mixture of (R)-(-)- and (S)-(+)-methadone, but (R)-methadone is the active isomer. The cytochrome P450 (CYP) isoform involved in methadone's metabolism is thought to be CYP3A4, but human drug-drug interaction studies are not consistent with this. The ability of the common human drug-metabolizing CYPs (obtained from baculovirus-infected insect cell supersomes) to generate 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrilidine (EDDP) from racemic methadone was examined and then determined if the CYP isoforms metabolized methadone stereoselectively. Only CYP2B6, 2C19, and 3A4 generated measurable EDDP from 1 microg/ml of racemic methadone. The hierarchy of EDDP generation was CYP2B6> CYP2C19 >/= CYP3A4. At 10 microg/ml of methadone, CYP2C9 and CYP2D6 also generated EDDP, but in at least 10-fold lower quantities than CYP2B6. Michaelis-Menten kinetic data demonstrated that CYP2B6 had the highest V(max) (44 ng/min/10pmol) and the lowest K(m) (12.6 microg/ml) for EDDP formation of all the CYP isoforms. In human liver microsomes with high and low CYP2B6 expression but equivalent CYP3A4 expression, high CYP2B6 expression microsomes generated twice the amount of EDDP from 10 microg/ml of methadone than low CYP2B6 expression microsomes. When stereoselective metabolism of racemic methadone by CYP2B6, 2C19, and 3A4 was examined using an enantiospecific methadone assay, CYP2B6 preferentially metabolized (S)-methadone, CYP2C19 preferentially metabolized (R)-methadone, and CYP3A4 showed no preference. These data suggest that multiple CYPs metabolized methadone but CYP2B6 had the highest V(max)/K(m). In addition, only CYP2B6 and 2C19 showed stereoselective metabolism. Our data could explain why the plasma concentration ratio of R/S methadone is variable and why drugs that induce CYP2B6 such as nevirapine and efavirenz also induce methadone metabolism, while the CYP3A4 inducer rifabutin has no effect on methadone pharmacokinetics.

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Thirty-two hospitalized patients diagnosed as schizophrenic were assigned in equal numbers to four groups on the basis of their scores on the Whitaker Index of Schizophrenic Thinking (WIST) and the paranoid (Pal scale of the MMPI. Subjects attempted to solve two conceptformation problems in which they were to identify relevant stimulus attributes, under two levels of demand on their memories for previous stimuli. Only in conjunction with a low score on the Pa scale did the schizophrenic index predict a conceptual deficit. Only the high-WIST, low-Pa group differed significantly from a control group of normal subjects. This result qualifies earlier research concerning the power of the WIST to predict logical performance. No difference was found between the two levels of memory demand.Conceptual behavior may be broadly defined as the collection of skills and knowledge that allows people to recognize regularities among objects and events, and to use those regularities to organize their cognitive representations of the world. Recent research (Bourne, Justesen , Abraham, Beeker, Brauchi, Whitaker, & Yaroush, 1977) has shown that the conceptual skills of a sample of patients diagnosed as schizophrenic varied as a function of the severity of schizophrenic thinking, as measured by the Whitaker Index of Schizophrenic Thinking (WIST) (Whitaker , 1973) .The WIST is a short (25-item) objective test that measures the illogicality of subjects' associations to single words, word pairs, and sentences that describe hypothetical inventions. Higher WIST indices indicate greater disturbance of thinking. In general, those patients who made unusual associations to the verbal stimuli on the WIST alsu failed to understand and abstract the relationship among visual stimuli required by a conceptual rule-learning task. Conspicuous,

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