Factors causing interindividual variations of drug concentrations in blood

Multiple factors in carefully controlled animal studies produce individual variations in drug blood levels. Since the hepatic microsomal enzyme metabolizing system is particularly sensitive to many environmental and genetically controlled factors, it is not surprising that variations in drug blood levels can be induced by any one of these numerous factors. Numerous factars can also alter drug absorption, distribution, and excretion, thereby exerting significant influence on blood drug levels. For several commonly used drugs, large interindividual variations in plasma half‐lives have been shown to be controlled predominantly by genetic fact ars in man. Both twin and family studies established these results for phenylbutazone, antipyrine, bishydroxycoumarin, ethanol, halothane, and nortriptyline. When a variety of environmental perturbations are imposed on this genetically controlled basal drug‐metabolizing capacity, alterations can also occur in drug absorption, distribution, and excretion. A commonly encountered example of environmental factors afJecting drug blood levels is coadministration of other drugs. Twin studies suggested that large interindividual variations in the response of plasma antipyrine half‐lives to phenobarbital were genetically controlled. Large variations also exist in the extent to which numerous drugs inhibit the metabolism of other drugs. Disease states can alter basal drug‐metabolizing capacity, e.g., in hyperthyroidism, drug‐metabolizing capacity is accelerated, and in hypothyroidism, retarded. Swiftly changing cardiovascular or renal status can also alter drug blood levels. In various disease states, the drug receptor site may become altered so that it no longer responds as expected to a given drug blood level. Operation of several of these factors in severely ill patients renders interpretation of drug blood levels difficult.