Drug disposition response variations

Gong IY, Rim RB (2013) Impact of genetic variation in OATP transporters to drug disposition and response. Drug Metab Pharmacokinet 28 4-18... 

Fig. 1 Sources of variability in drug response in children. These include factors inherent to the child, the effect(s) of the disease being treated or other diseases, the effects of other therapies, ontogeny, and genetically controlled variation in drug disposition, action, and clearance...

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). 

It is recommended that LD q be determined in mice and rats, and MTD be determined in dogs and monkeys. Drug disposition studies and plasma level determinations should be performed in these species after parenteral administration of the LDio, half the LDiq, and one-tenth the LD o. The area under the serum curve for the various doses should bear a linear relationship to the dose in mg/m or to the dose in mg/kg x If these relationships hold for the different laboratory species, they are likely to hold for man. If reasonably linear relationships do not obtain, it suggests that unique metabolic pathways may exist in some species, or that the enzymatic process may have been overwhelmed by virtue of high tissue levels of the drug [23]. Stated in another way, if one sees great variations in the response of experimental animals that bear no relationship to the size of the animals, then it is unlikely that any prediction can be made for man. On the other hand, where these relationships can be established, it seems possible that an inter-species dose-response phenomena intimately tied to plasma levels can be constructed. 

As shown in Figure 1-2, of the four factors (absorption, distribution, metabolism, and excretion) that together determine the fate and disposition of most drugs, variability in metabolism is most substantial and usually is the reason for interindividual and crossethnic variations in drug responses (Lin and Poland 1995). Most drugs are metabolized in two phases. Phase I, commonly mediated by one or more of the cytochrome P450 (C YP) enzymes, leads... 

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