Ethnic differences in metabolism

One approach to formulating potential differences in ethnic response is to examine the metabolic pathways of the common antipsychotics and determine whether the known ethnic variations in metabolizing enzymes or other effects on absorption, distribution, and excretion can be applied a priori to predict potential clinical effects. In this section we will consider some of the commonly prescribed SGAs, and only briefly touch on the FGAs. 

Ethnic differences in CYP2D6 have been more thoroughly documented than with the other isoenzyme (Bradford, 2002). Over 70% of Caucasians but only about half of Asians, Sub-Saharan Africans, and African Americans have fully functional CYP2D6 alleles - alleles that code for normal metabolic activity. Approximately 50% of Asian and people of African ancestry have reduced function or nonfunctioning alleles. As a consequence, many older psychotropic medications are metabolized more slowly and plasma levels would be higher. Thus individuals of African and Asian ancestry would have an increased risk of side effects and should receive lower dose for a therapeutic response when compared to Caucasians of European descent (Lin, 2001 Lawson, 2000). 

Benowitz ML, Jacob P 3rd, Fong I, Gupta S (1994) Nicotine metabolic profile in man comparison of cigarette smoking and transdermal nicotine. J Pharmacol Exp Ther 268 296-303 Benowitz NL, Perez-Stable EJ, Eong 1, Modin G, Herrera B, Jacob P 3rd (1999) Ethnic differences in N-glucuronidation of nicotine and cotinine. J Pharmacol Exp Ther 291 1196-1203 Benowitz NL, Griffin C, Tyndale R (2001) Deficient C-oxidation of nicotine continued. Chn Pharmacol Ther 70 567... 

Inter-ethnic differences in drug metabolism have become a trendy, and often quite exciting, line of enquiry. Results have often been quite surprising. For... 

These are a few illustrations of the emerging pattern of inter-ethnic differences in drug metabolism, which is genetically determined. 

Schneider L, Pawluczyk S, Dopheide J, Lyness SA, Suckow RF, Copper TB (1991) Ethnic differences in protriptyline metabolism. New Research Program and Abstracts, American Psychiatric Association 144th Annual Meeting, New Orleans. American Psychiatric Press... 

Kalow W, Otton SV, Kadar D, Endrenyi L, Inaba T. Ethnic difference in drug metabolism debrisoquine 4-hydroxylation in Caucasians and Orientals. Can J Physiol Pharmacol 1980 58 1142-1144. 

Kalow W. Ethnic differences in drug metabolism. Clin Pharmacokinet 1982 7 373 100. 

In some cases, biological reasons for ethnic differences in drug-metabolizing capacity have been established, but usually they are not understood. 

Anderson KE, Conney AH, Kappas A. Nutrition as an environmental influence on chemical metabolism in man. In Kalow W, Goedde HW, Agarwal DP, eds. Ethnic Differences in Reactions to Drugs and Xenobiotics. New York Alan R. Liss Inc., 1986 39-54. 

Race and ethnicity may also be risk factors for ADRs. Prior personal or family history of ADRs may be predictive of future adverse reactions. Genetic polymorphisms for many metabolic reactions are described in Chapter 13 and have been well documented (45). Prescribing some medications without regard to genetic differences in metabolism can result in therapeutic failures or drug toxicity (45, 46). For example, differences in acetylator phenotype can alter the metabolism of some drugs and influence the risk of certain adverse reactions. Slow acetylators, for example, may be more likely than rapid acetylators to develop he pa to toxicity from isoniazid treatment. The biochemical basis for this difference is described in Chapter 16. 

These differences in clinical response and pharmacokinetics have been attributed to ethnic differences in drug metabolism mediated through the cytochrome P450 microsomal enzyme system, which is responsible for the metabolism of most of the older psychotropic medications, including typical antipsychotics and TCAs (Lin et al. 1993 Silver et al. 1993). Earlier studies showed that Caucasians were more likely than Asians and African Americans to be poor metabolizers of psychotropic medication, a finding inconsistent with clinical experience, because poor metabolizers should require less medication. However, new mutations have recently been discovered in the enzymatic systems of the latter groups that are intermediate in the rate of metabolism. Thus, up to 47%-70% of African Americans and Asian Americans may be slow metabolizers, which could account for the higher incidence of side effects (Mendoza et al. 1999). 

Zhang Y, Bertilsson L, Lou T, et al., 1990. Diazepam metabolism in native Chinese, poor and extensive hydroxylators of S-mephenytoin inter-ethnic differences in comparison with White subjects . Clin. Pharmacol. Ther. 48 496—502. 

Rare individuals appear to be deficient metabolizers of nicotine. Individual differences are described both in the pattern and rates of nicotine metabolism. Ethnic differences in cotinine metabolism have also been observed. However, the enzymes responsible for nicotine metabolism and their genetic regulation have not been fully characterized. Understanding the basis for individual differences in nicotine kinetics and metabolism, and linking these differences to... 

FDA/PhRMA/Johris Hopkins University of various alleles with no or reduced en-educational workshop [64]. Because of 2yme activities for various metabolizing race/ethnic differences in the distribution enzymes [25-27], it is important to consid-... 

---