6. Dose Adjustments Based on Pharmacogenetics of CYP450 Enzymes

In today’s medicine, drug therapy represents an important tool to treat or control disease. Dosing drugs is based on the assumption that a particular dose will yield a predefined concentration in the circulation and thereby establish the desired therapeutic effect. The fact that liver and kidney function may affect this relationship is appreciated, as is the fact that the use of co-medication potentially may interfere with the relationship between dose and blood concentration. Also environmental factors, like diet, alcohol use, smoking behaviour and caffeine intake may alter the rate at which particular drugs are metabolized, and will thus affect exposure of individuals to these drugs. A factor that has been neglected for a long time is genetics: differences in genetic make up may affect the relation between drug dose and blood concentration. Variant alleles encoding drug transporters or drug metabolizing enzymes with altered activity, present in the population, will give rise to unexpectedly high or low blood concentrations in response to a particular dose of a drug in certain individuals. The variation in drug metabolizing capacity between individuals is known for quite some time, but only recently this is becoming available as a routine diagnostic to provide better therapy. An important group of enzymes involved in drug metabolism is the cytochrome P450 enzyme system, which is mainly (but not only) active in the liver and the intestine. It consists of a family of isoenzymes, each with their own substrate specificity, and catalyzes oxidative reactions in order make potentially toxic and harmful substances more soluble. Purpose is to protect the body against toxic substances. The most important cytochromes with respect to drug metabolism are CYP3A4, CYP2C9, CYP2C19 and CYP2D6. For these enzymes, however, several variant alleles encoding enzymes with decreased activity exist (see www.cypalleles.ki.se), giving rise to interindividual differences in capacity to metabolize drugs. The best known example in this family is the enzyme CYP2D6, for which even 10% of the Caucasian population is a poor metabolizer, due to inheritance of two inactive variant alleles.