Bufuralol

Replacement of isopropylamine by tert-butyl amino often results in an increase in potency. This substitution is used in the p-blockers bunitrolol (116),54 bufuralol (117),55 bunolol (118),56 nadolol (119),57 and phenbutalol (120).58 Tazolol (121)59 whose structure is similar, is not a good p-blocker, possessing substantial ISA. 

Figure 7.5 Mucosal-to-submucosal (m-s), Tapp values across human buccal culture of midazolam (CYP3A4 substrate), bufuralol (CYP2D6 substrate), tolbutamide (CYP2C9 substrate), and the nonmetabolized, high-permeability control compound caffeine (average SEM, N = 1 — 3 replicates). (Asterisk) in the presence of CYP inhibitors (CYP3A4-ketoconazole CYP2D6-quinidine CYP2C9-suphaphenazole). In all treatments integrity of the culture was verified by permeation of Lucifer yellow (< 2.0 x 10-6 cm/s). Results from internal study by Absorption Systems Company.

Bucainide, 125 Bucloxic acid, 126 Buformin, 21 Bufuralol, 110 Burnetanide, 87 Bunaftine, 211 Bunamidine, 212 Bunitridine, 215 Bunitrolol, 106, 110 Bunolol, 110, 215 Bupicomide, 280 Buprenorphine, 321 Bupropion, 124 Burimamide, 251 Buspirone, 300 Butacetin, 95 Butamirate, 76 Butaclamol, 226 Butorphanol, 325 Butropium bromide, 308... 

P. (1986) The molecular mechanisms of two common polymorphisms of drug oxidation—evidence for functional changes in cytochrome P-450 isozymes catalysing bufuralol and mephenytoin oxidation. Xenobiotica 16, 449-464. 

D6 Bufuralol, bupranolol, clomipramine, clozapine, codeine, debrisoquin, dextromethorphan, encainide, flecainide, fluoxetine, guanoxan, haloperidol, hydrocodone, 4-methoxy-amphetamine, metoprolol, mexile-tine, oxycodone, paroxetine, phenformin, propafenone, propoxyphene, risperidone, selegiline (deprenyl), sparteine, thioridazine, timolol, tricyclic antidepressants Unknown Quinidine, paroxetine... 

Oxidation CYP2D6 Bufuralol (3-adrenoceptor blocker) Exacerbation of 3 blockade, nausea... 

As an example of the first type of chiral effect, metabolism of the drug bufuralol may be considered. Hydroxy la tion in the V position only occurs with the (+) isomer, whereas for hydroxylation in positions 4 and 6, the (—) isomer is the preferred substrate (Fig. 5.3). Glucuronidation of the side chain hydroxyl group is specific for the (+) isomer. A further complication in human subjects is that the 1-hydroxylation is under genetic control, being dependent on the debrisoquine hydroxylator status (see below). The selectivity for the isomers for the hydroxylations is virtually abolished in poor metabolizers. 

Figure 5.3 The hydroxylation of the drug bufuralol. The arrows show (A) the site of V hydroxylation and (B) the site of glucuronidation.

As with the hydroxylation of bufuralol, the hydroxylation is stereo-selective. Thus, only S-mephenytoin undergoes aromatic 4-hydroxy lation, and only this route is affected by the polymorphism. The R isomer undergoes N-demethylation. Poor metabolizers may suffer an exaggerated central response when given therapeutic doses (Fig. 5.29). 

D6 Debrisoquine, sparteine, bufuralol, propanolol, thioridazine, quinidine, phenytoin, fluoxetine NNK3 Dextromethorphan, [bufuralol (4 -OH)... 

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