PHARMACOKINETICS AND PHARMACODYNAMICS

Proteins affect drug concentration (pharmacokinetics) and response (pharmacodynamics). Historically, genetic variation most often has been identified in pharmacokinetics, particularly in drug metabolizing enzymes.⁶ Genetic variation in the pharmacokinetic profile often necessitates a change in the dosage regimen of a drug, but not in its selection. Pharmacogenetic differences in drug target responsiveness²⁸ are less well understood, but potentially will also have a significant impact on patient outcomes in the future. In these instances, certain drugs would be contraindicated for patients with particular genotypes. Just as drug prescribers are currently responsible for avoiding adverse “drug-drug” interactions, as described in Appendix 1, they increasingly will be held accountable for avoiding untoward “gene-drug” interactions in clinical practice. Genetic differences in pharmacokinetics and pharmacodynamics are anticipated for many, if not most, drugs, yielding important consequences for drug responsiveness, especially for agents with a narrow therapeutic index. Figure 4-2 illustrates the separate and combined influences of genetic polymorphisms in pharmacokinetics and pharmacodynamics.¹⁴

FIGURE 4-2 The potential consequences of administering the same dose of drug to individuals with genetic polymorphisms in both pharmacokinetics (drug-metabolizing enzymes) and pharmacodynamics (drug receptors). Active drug concentrations in the systemic circulation are determined by the individuals’ drug metabolism genotype, with (A) homozygous common (c/c) genotype converting 70% of a dose to the inactive metabolite, leaving 30% to exert an effect on the target receptor. B, For the patient with heterozygous (c/v) drug metabolism genotype, 35% is inactivated, whereas (C) the patient with homozygous mutant (v/v) drug metabolism inactivates only 1% of the drug dose, yielding the three drug concentration time curves. The drug response is further influenced by drug receptor genotypes. Patients with a c/c receptor genotype exhibit a greater therapeutic effect (solid lines) at any given drug concentration in comparison to those with a c/v receptor genotype, whereas those with v/v receptor genotypes are relatively refractory to drug effects at any plasma drug concentration. The combination of genetic polymorphisms in drug metabolism and receptor yields nine different theoretical patterns of drug effect. The therapeutic ratio (efficacy versus toxicity) ranges from very favorable in a patient with c/c genotypes for drug metabolism and drug receptor to very unfavorable in the patient with v/v genotypes. (It is assumed here that the toxic dose-response curve, shown in dotted lines, is not influenced by these polymorphisms.)

(Redrawn from Evans WE, Relling MV: Pharmacogenomics: translating functional genomics into rational therapeutics, Science 286:487-491, 1999.)

There are many gene-drug interactions with importance to dentistry. Codeine, one of the mostly commonly prescribed opioid analgesics for pain relief, is a prodrug and depends on its activation to morphine by CYP2D6, a drug-metabolizing enzyme that is known to exhibit a common genetic polymorphism in humans.⁴⁸ As a result, codeine is an ineffective analgesic in a significant genetic subset (10%, depending on ethnic group) of the population. Genetic polymorphisms in opioid receptors or in second messenger systems mediating opioid receptor actions have also been observed. If a patient inherits a deficiency in CYP2D6 or the μ-opioid response system, it is unlikely that standard doses of codeine will be of therapeutic benefit. Increasing the dose of codeine to compensate for the genetic deficiency will most likely result not in analgesia but rather in an adverse reaction mediated by overstimulation of an alternative receptor that is responsive to codeine.

PHENOTYPE AND GENOTYPE

An individual’s genotype is a genetic trait defined by the DNA sequences (i.e., alleles) inherited from the mother and the father. An individual can inherit two copies of the same allele (homozygous genotype) or a different allele from each of the parents (heterozygous genotype). The phenotype is a biologic or measurable expression of the genetic trait that depends on the level of penetrance of the gene, the accuracy and selectivity of the method used to measure it, and the influence of environmental factors in the expression of the trait. Historically, one of the most easily measured phenotypes was plasma drug concentration, which is probably why most of the initially identified pharmacogenetic traits were pharmacokinetic phenotypes. Determination of drug concentration is invasive, however, requiring administration of a drug or surrogate chemical and collection of blood samples over time. The drug concentration also depends to varying degrees on patient age, general health, nutritional status, and other factors such as exposure to enzyme inducers and inhibitors. Determination of a patient’s genotype is much less invasive because it does not require administration of a test drug or collection of blood samples over time. Instead, the genotype is determined from a small sample of DNA obtained easily from a buccal swab, hair follicle, or other ready source, and is not affected by age, general health, nutritional status, or other factors. For these same reasons, the prediction of drug response from a genetic test may not always be accurate or reproducible because of the influence of such nongenetic factors on drug response.

Many methods to determine the genotype have been developed in the past two decades, including restriction fragment length polymorphism analysis, allele-specific amplification, and DNA sequencing. Most methods rely on DNA amplification techniques based on the polymerase chain reaction that yield millions of copies of the specific target gene. New high-throughput methods promise to make the simultaneous determination of multiple genotypes readily available to health care professionals.⁵² Understanding the important and complex relationships between genotypes and phenotypes has fostered much research in functional genomics and proteomics.

MONOGENIC VERSUS POLYGENIC PHENOTYPES

A discussion of genetic polymorphisms in enzymes and receptors would be incomplete without consideration of the differences inherent between monogenic and polygenic phenotypes. Monogenic phenotypes derive from genetic variations in a single gene. Monogenic variation often separates populations into discontinuous (bimodal or trimodal) distributions of the phenotype. If the least commonly occurring phenotype arising from the monogenic variation has a frequency of greater than 1% in a population, it is termed a polymorphism. Different drugs or dosing regimens may be appropriate for specific phenotypes. Polygenic traits, in contrast, are phenotypes that derive from some combination of variations in multiple genes. In this case, clearly distinct or discontinuous phenotypes are not observed in a studied population. Instead, there is a unimodal, continuous, normal (Gaussian) distribution of the phenotype. A unimodal distribution of drug response is observed for most drugs metabolized by multiple enzymes, transported by multiple proteins, or acting through multiple receptors or second messenger systems. This unimodal distribution does not mean an absence of genetic variation in one or all of these proteins, but rather that multiple genes contribute to the overall drug response phenotype. Because each of the genes is potentially subject to genetic variation, the utility of genetic information in predicting therapeutic and toxic responses is considerably more complicated. Until recently, polygenic phenotypes were too complex to consider in optimizing drug therapy.

ETHNIC DIFFERENCES IN PHARMACOGENETICS

The frequency of specific alleles, genotypes, and phenotypes for drug metabolizing enzymes varies widely with ethnic origin.²⁹ A similar variance is expected for drug receptors. Clinical trials are best conducted either with ethnically diverse study populations to capture differences among ethnic groups with ethnically defined subgroups to define effects in these groups precisely. Some genotyping methods were designed originally to identify only alleles prevalent in whites. With the documented ethnic heterogeneity within the human population, however, genotyping tests need to identify all relevant alleles of a particular gene regardless of ethnic frequency.

PHARMACOGENETICS OF DRUG METABOLISM

As indicated earlier, most of the pharmacogenetic traits identified to date occur in genes encoding drug metabolizing enzymes. It is anticipated that genetic polymorphisms may be identified in all drug metabolizing enzymes. Many of these genetic polymorphisms are already known to be important in therapeutics,⁶³ and examples of historical and clinical interest are highlighted next.