Genetically determined variation

Effects of Genetically Determined Variation in Nicotine Metabolism on the Development of Nicotine Dependence... 

Individual genetically determined variations in transporter function may contribute to interindividual differences in therapeutic and/or adverse effects of drugs. Several studies have shown that variations in transporter gene sequences do occur. However, the clinical significance of these variations generally is not yet well documented. For example, as discussed in Chapter 4, the intestinal hPEPT-1 transporter plays a role in absorption of peptide-like cephalosporin antibiotics and other drugs. Interindividual variations in hPEPT-1 may account for the large interindividual variations in bioavailability that have been observed (129). 

VESELL, E.S. (1975) Genetically determined variations in drug disposition and response in man. In Handbook of Experimental Pharmacology, edited by J.R.Gillette and J.R.Mitchell (Berlin Springer). 

Pharmacogenetics involves the impact of genetic variation on drug response. The link between genetically determined variation in drug metabolism enzymes (e.g., cytochrome p450, N-acetyltransferase) and intersubject differences in pharmacokinetics is well established. Likewise, there is an increasing awareness that differences in transporter expression can impact the efficacy and safety of pharmacotherapy. 

Genetically determined variations in the distribution of lithium between plasma and erythrocytes have been found in sheep (Schless et. al. 1975). Likewise, depressive patients react differently to lithium treatment, with heredity a probable contributory factor, as has been shown investigations conducted in twins. A hereditary recessive primary hypomagnesemia that is accompanied by a low level of calcium in the blood leads to tetany. This is presumably caused by a nonfunctional magnesium resorption in the intestine (Lombeck and Bremer... 

Amino acid substitutions in the primary structure. Mutations in the genetic code result in proteins with an altered primary structure. Mutations resulting in single amino acid substitutions can affect the functioning of a protein or can confer an advantage specific to a tissue or a set of circumstances. Many proteins such as hemoglobin exist in the human population as polymorphisms (genetically determined variations in primary structure.)... 

The term phenocopy refers to an environmentally induced variation that closely resembles a genetically determined variation. For example, dietary vitamin B deficiency is a phenocopy of the inherited disorder, methylmalonic acidemia and homocystinuria due to cobalamin C disease. Both dietary vitamin B,2 deficiency and cobalamin C disease have the biochemical findings of elevated plasma methylmalonic acid and homocysteine levels. Awareness of phenocopies is important as they provide an alternative explanation for clinical findings. For example, in the case of elevated... 

The metabolism and action of many other drugs also show genetically determined variations, e.g. parahydroxylation of diphenylhydantoin, insulin antagonism in serum, rigidity and hyperthermia in anaesthesia, response to antidepressive drugs, phenothiazine-induced extrapyramidal disorders, hypersensitivity and resistance to vitamin D therapy and drug reactions in hereditary porphyria. 

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