ABSTRACT:There are documented clinical drug-drug interactions between bupropion and the CYP2D6-metabolized drug desipramine resulting in marked (5-fold) increases in desipramine exposure. This finding was unexpected as CYP2D6 does not play a significant role in bupropion clearance, and bupropion and its major active metabolite, hydroxybupropion, are not strong CYP2D6 inhibitors in vitro. The aims of this study were to investigate whether bupropion's reductive metabolites, threohydrobupropion and erythrohydrobupropion, contribute to the drug interaction with desipramine. In human liver microsomes using the CYP2D6 probe substrate bufuralol, erythrohydrobupropion and threohydrobupropion were more potent inhibitors of CYP2D6 activity (K i ‫؍‬ 1.7 and 5.4 M, respectively) than hydroxybupropion (K i ‫؍‬ 13 M) or bupropion (K i ‫؍‬ 21 M). Furthermore, neither bupropion nor its metabolites were metabolism-dependent CYP2D6 inhibitors. Using the in vitro kinetic constants and estimated liver concentrations of bupropion and its metabolites, modeling was able to predict within 2-fold the increase in desipramine exposure observed when coadministered with bupropion. This work indicates that the reductive metabolites of bupropion are potent competitive CYP2D6 inhibitors in vivo and provides a mechanistic explanation for the clinical drug-drug interaction between bupropion and desipramine.Bupropion is a norepinephrine/dopamine reuptake inhibitor currently indicated for the treatment of major depressive disorder (Wellbutrin; GlaxoSmithKline, Research Triangle Park, NC) and smoking cessation (Zyban; GlaxoSmithKline). Clinical interactions involving bupropion and coadministered CYP2D6 substrates desipramine (Shad and Preskorn 1997;Jefferson et al., 2005), dextromethorphan (Güzey et al., 2002;Kotlyar et al., 2005), and venlafaxine (Kennedy et al., 2002) are well documented. However, CYP2D6 plays an insignificant role in bupropion clearance. In humans, bupropion is extensively metabolized to three active metabolites: hydroxybupropion, which is formed primarily via CYP2B6, and the amino-alcohol isomers threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group (Schroeder, 1983;Golden et al., 1988;Faucette et al., 2000;Hesse et al., 2000). Presumably, the mechanism for the clinical interaction with desipramine, which is primarily eliminated via CYP2D6 (Gram, 1974;Distlerath and Guengerich, 1984;Brøsen et al., 1986), is the result of CYP2D6 inhibition by bupropion and/or its metabolite(s). However, published data show that bupropion and hydroxybupropion are weak CYP2D6 inhibitors in vitro (IC 50 ϭ 58 and 74 M, respectively) (Hesse et al., 2000). Because unbound human plasma concentrations of the active metabolites are 2.3-to 12-fold higher than bupropion levels, it is possible that the CYP2D6 inhibition observed in the clinic is the result of more potent CYP2D6 inhibition by threohydrobupropion or erythrohydrobupropion compared with bupropion and hydroxybupropion. In addition, another hypothesis...

1. Human urine samples from a clinical trial of the anti-HIV compound (-)-cis-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]-cyto sin e (BW524W91) have been analysed using 19F-nmr and 1H-hplc-nmr spectroscopy. 2. The identities and relative levels of the xenobiotic species in the urine have been determined by 470-MHz 19F-nmr spectroscopy and by directly coupled 600-MHz 1H-hplc-nmr in the stop-flow mode with confirmation of the metabolite identities being made by comparison with nmr spectra of synthetic standard compounds. 3. The principal urinary xenobiotic was the unchanged drug, but the glucuronide ether conjugate at the 5' position of BW524W91, one of the two diastereomeric sulphoxides and the deaminated metabolite were also characterized. 4. The detection limit of directly coupled hplc-600-MHz 1H-nmr spectroscopy was evaluated by measuring two-dimensional nmr spectra of the glucuronide conjugate of BW524W91 and shown to be approximately 1 microgram material for 1H-1H-TOCSY and 20 micrograms metabolite for 1H-13C-HMQC spectra for overnight (16 h) acquisition.

1. The metabolism of 1-ethylphenoxathiin-10,10-dioxide (BW1370U87), an experimental compound designed as an inhibitor of monoamine oxidase-A for use as a possible anti-depression agent, has been studied in a human liver microsome preparation. 2. The identities of the metabolites have been determined using directly coupled hplc-1H nmr at 600 MHz in the stop-flow mode in this first study of in vitro xenobiotic metabolism using hplc-nmr. 3. The xenobiotic substances that were identified comprised the parent compound BW1370U87 (with -CH2CH3 at C1) together with sidechain-oxidized metabolites with C1 substituents of -CHOH.CH3, -CH2.CH2OH, -CHOH.CH2OH and -CH2.COOH, plus the unsubstituted phenoxathiin-10,10-dioxide.

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