ministered, interactions may occur such as those observed with nortriptyline, an antidepressant drug, and a barbiturate. In part of the study, all subjects were given nortriptyline three times a day for 8 days and all had attained a steady-state concentration of the drug. Identical twins not ingesting other drugs exhibited considerable intertwinship variation but relatively small intratwinship variation. Fraternal twins not ingesting other drugs also exhibited considerable intertwin-ship variation, and for most twinships (8 out of 12) the intratwinship variability was small, as for identical twins. In 4 out of 12 fraternal twinships, however, there were large intratwinship differences. This finding suggests relatively small numbers of allelic genes are segregating.

Nortriptyline metabolism can be increased by the action of other drugs, especially the barbiturates. In another part of the study referred to above, twinships were encountered in which one or both members were on drug medication, in several instances, barbiturates. Identical twinships in which members were being given other drugs exhibited large twinship variability in nortriptyline steady-state concentrations, and this effect was magnified even more in fraternal twinships in which some members were receiving other drugs. These observations indicate that the nortriptyline steady-state concentration, an index of the individual's capability to metabolize the drug, is the result of genetic constitution and environment (exposure to other drugs), but that heredity exerts a very important influence on the interaction.

To look further into the pharmacogenetics of such interactions, a separate twin study with a barbiturate (phenobarbital) and another drug, antipyrine, was performed. This study revealed that the plasma half-life of antipyrine after phenobarbital was significantly reduced in both identical and fraternal twins, but again the intrapair differences were significantly less in identical than in fraternal twins (Table 5.4).22

Identical and fraternal twins are valuable resources for studying the relative importance of heredity and environment. Unfortunately, the genetic interpretation of twin studies may give rise to imprecise estimates of heritability. Furthermore, twin studies do not discriminate between different patterns of inheritance. Because similar drug effects may occur in different persons in similar environments, it is important to study twins who have been reared apart, and who have been exposed to environments as dissimilar as possible.

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