Metabolism and pharmacogenetics
Although the primary pathways of drug metabolism have been understood for at least 20 to 25 years, the extent and mechanisms of drug inter actions and pharmacogenetic influences on blood concentrations have only really been elucidated in the past few years. A detailed discussion of pharmacogenetics and drug metabolism is beyond the scope of this chapter; however, some aspects should be highlighted. It is known that 7–8% of the caucasian population aredeficientincytochrome-P450IID6(P450IID6), one of the major enzymes responsible for many important oxidative pathways, such as alkyl hydroxylation. That deficiency is determined genetically. As a result, the ability of those affected to metabolise and clear many drugs may be affected seriously. In many instances, even though drug clearance is significantly slower than for those not deficient in P450IID6, it is not as slow as might be predicted because other pathways may compensate. Even if a person is not specifically identified as being deficient in P450IID6, the person or physician may be indirectly aware of it because of an unusual sensitivity to some drugs and the higher prevalence of side-effects. Even in people without deficiencies in drug-metabolising enzymes, drug–drug interactions can result in dangerously elevated concentrations. It has also been recognised that many drugs can inhibit their own metabolism by saturating the primary metabolising enzyme systems. For example, the dose–plasma concentration curve for phenytoin can rise almost exponentially at high therapeutic doses. These variabilities in the relationship between dose and plasma or blood concentration can therefore introduce even more error into any attempt to apply conventional pharmacokinetics to estimate dosage.
There is a great temptation to categorise blood levels in black-and-white terms as being the result of therapeutic doses, or of a suicidal over dose, or perhaps of abuse. Other possibilities are sometimes overlooked when high concentrations of drugs are encountered. One of the simplest ways to determine compliance with prescribed dosage, although not foolproof, is to conduct a medication count. Knowing when the medication was prescribed, how much was dispensed, the dose and the number of days between dispensing and death can often provide a powerful indicator of patient compliance, and whether an overdose is likely or not. Information regarding compliance over a longer period may often be obtained by a review of the pharmacy or medical records. The slowing of drug metabolism with age has been well documented, but this can be overlooked as an explanation for elevated postmortem drug concentrations in the elderly.
