Hydroxylator status

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. 

N-acetyltransf erase, NAT2) hydroxylation status (CYP2D6 CYPC19) esterase deficiency (pseudocholinesterase). 

Koyama E, Tanaka T, Chiba K, et al Steady-state plasma concentrations of imipramine and desipramine in relation to S-mephenytoin 4 -hydroxylation status in Japanese depressive patients. J Clin Psycho-pharmacol 16 286-293,1996... 

The importance of such polymorphisms in human susceptibility to diseases, such as cancer, is now increasingly being recognized. For example, studies in humans with amino biphenyl, a liver and bladder carcinogen, have shown that both the acetylator phenotype and hydroxylator status are important in the formation of adducts (see Chapter 6). 

Genetic factors are particularly important in humans and can influence the response to the compound or the disposition of the compound and hence its toxicity. Several genetic factors affecting metabolism are known in which a non-functional or less functional form of the enzyme is produced in a particular phenotype, e.g. acetylator phenotype (N-acetyltransferase NAT2) hydroxylator status (cytochrome P-450 2D6) esterase deficiency (pseudocholinesterase). 

Yasuda, S. Horai, Y. Tomono, Y Nakai, H. Yamato, C. Manabe, K. Kobayashi, K. Chiba, K. Ishizaki, T. Comparison of the kinetic disposition and metabolism of E3810, a new proton pump inhibitor, and omeprazole in relation to S-mephenytoin 4 -hydroxylation status. Clin.Pharmacol.Ther., 1995, 58, 143-154 [LOQ 5 ng/mL pharmacokinetics]... 

In any case, drawing the structure of a given ceramide is quite easy, provided that both the nature and hydroxylation status of the acyl chain are clearly indicated. In Fig. 1.21 you have... 

Peak plasma concentration appears within 1 to 6 h depending on fasted or fed status. There is 99% binding of tenoxicam to plasma proteins and a long plasma elimination half-life of 49 to 81 h. Tenoxicam is eliminated by liver metabolism. The main metabolites are 5 -hydroxy-tenoxicam and the 6-O-glucuronidate which are excreted in urine and bile, respectively (Nilsen, 1994). The hydroxylated metabolites of tenoxicam are shown in Scheme 84 ... 

Sohn DR, Kwon JT, Kim HK, et al. Metabolic disposition of lansoprazole in relation to the S-mephenytoin 4 -hydroxylation phenotype status. Clin Pharmacol Ther 1997 61 574-582. 

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