Metabolic polymorphisms

Lou, Y.C. (1990). Differences in drug metabolism polymorphism between Orientals and Caucasians. DrugMetab. Rev., 22, 451-75. 

A5. Allison, A. C., Metabolic polymorphisms in mammals and their bearing on problems of biochemical genetics. Am. Naturalist 93, 5 (1959). 

Wedlund, P.J., Aslanian, W.S., McAllister, C.B., Wilkinson, G.R. and Branch, R.A. (1984) Mephenytoin hydroxylation deficiency in Caucasians frequency of a new oxidative drug metabolism polymorphism. Clinical Pharmacology and Therapeutics, 36 (6), 773-780. 

Probabilistic methods can be applied in dose-response assessment when there is an understanding of the important parameters and their relationships, such as identification of the key determinants of human variation (e.g., metabolic polymorphisms, hormone levels, and cell replication rates), observation of the distributions of these variables, and valid models for combining these variables. With appropriate data and expert judgment, formal approaches to probabilistic risk assessment can be applied to provide insight into the overall extent and dominant sources of human variation and uncertainty. 

Humans differ in sensitivity due to biological factors such as metabolic polymorphism, age, gender, health status, and nutritional status. These differences can be the result of genetic and/or environ-mental/behavioral influences. This intraspecies (interindividual) variation is greater in humans than in the more inbred experimental animal population. 

Wedlund PJ, Aslanian WS, McAllister CB. Mephenytoin hydroxylation deficiency in Caucasians frequency of a new oxidative drug metabolism polymorphism. Clin Pharmacol Ther 1984 36 773-780. 

Motulsky AG. Metabolic polymorphisms and the role of infectious diseases in human evoluation. Hum Biol 1960 32 28. 

Keywords QM/MM, molecular dynamics, transition state, drug metabolism, polymorphism,... 

Metabolic polymorphisms affect the rate of clearance of certain drugs. A good example can be seen in the pharmacogenetics haloperidol in poor and extensive metabolizers of CYP2D6 (Figure 11.2). If a drug has a narrow therapeutic index (ratio of toxic dose/therapeutic dose), the polymorphism may produce toxic levels in the PM (Figure 11.3). 

Vineis, P., Malats, N., Lang, M., d Errico,N., Caporaso,N., Cuzick, J., and Boffetta, P. Metabolic Polymorphisms and Susceptibility to Cancer, IARC Scientific Publications 148, Lyon, France, 1999. 

Smith G, Stanley LA, Sim E, Strange RC, Wolf CR. Metabolic polymorphisms and cancer susceptibihty. Cancer Surv 1995 25 27-65. 

Baumann P, Jonzier Percy M, Koeb L, etal. Amitriptyline pharmacokinetics and clinical response II. Metabolic polymorphism assessed by hydroxylation of debrisoquine and mephenytoin. Int Clin Psychopharmacol 1986 1(2) 102-12. 

Tricker, A.R. (2003). Nicotine metabolism, human drug metabolism polymorphisms, and smoking behaviour. Toxicology 183, 151-173. 

These PBPK/PD models provide a reasonably good prediction of dosimetry and biological response, but it is important to recognize that the predictive capabilities of these models are limited by the adequacy of the parameters and limitations of the experimental data (Timehalk et a 2002b), However, it is anticipated that tliese basic structures can be used as a starting point for the development of other OP and CM insecticide models. Once validated, these modeis can then be used to understand complex mixture interactions, sensitive subpopuiations, and the role of metabolic polymorphisms in altering dosimetry and biological response. 

Kusano, K., Seko, T., Tanaka. S., Shikaia, Y. Ando, T, Ida. S., Hosokawa, M.. Satoh, T. Yuzuriha, T.. and Horic, T. (1996). Purification and characterizaiion of monkey liver amidohydro-lascs and its relationship to a metabolic polymorphism of E6123, a platelet activating factor receptor antagonist. Drug Metab. Dittos., in press. 

Kusano K, Seko T, Tanaka S, et al. (1996). Purfication and characterization of Rhesus monkey liver amido hydrolases and their roles in the metabolic polymorphism for E6123, a platelet-activating factor receptor antagonist. Drug Metabol. Dispos. 24 1186-1191. 

Daly AK, Cholerton S, Gregory W, et al. Metabolic polymorphisms. Pharmacol Ther 1993 57 129-160. 

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