Polymorphisms: Why Individual Drug Responses Vary

Gastrointestinal Tract

Extrinsic and intrinsic factors can result in altered absorption in the gastrointestinal (GI) tract. Antacids raise the stomach’s pH, which can influence medication absorption. Ketoconazole is a classic example of a medication that is better absorbed in an acidic environment ( Table 3.1 ). Other medications can act as binding resins in the GI tract, and thus inhibit absorption. There is evidence that iron will bind mycophenolate mofetil, thereby inhibiting its absorption (see Table 3.1 ). GI transit times are thought to play only a small role in drug absorption variability. Anticholinergic agents and opioids can slow down transit times, whereas infections and some medical conditions such as Crohn’s disease and ulcerative colitis can markedly increase transit times.

P-Glycoprotein

P-glycoprotein (PGP), a membrane-bound transport protein, affects drug absorption in the GI tract. Functioning as part of the ‘first-pass effect’ in the gut, PGP acts as a pump to remove drugs from the cell through active adenosine triphosphate (ATP) hydrolysis. Cyclosporine is just one example of a medication in which PGP can affect drug bioavailability (see Table 3.1 ). High levels of PGP are also found in the kidneys and liver, where it functions in drug elimination.

Nomenclature

CYP enzymes are classified by a hierarchical nomenclature system. The first number represents the enzyme family followed by a letter designating the subfamily. The final number is for the individual gene. There is at least 40% homology in amino acid sequences within a family, whereas subfamilies have 77% or more homology.

Q3.2 Although there are more than 50 families of CYP enzymes, only a few CYP isoforms (CYP1A2, 2B6, 2C9, 2C19, 2D6, 2E1, 3A4) appear to play a significant role in drug metabolism ( Table 3.2 ). Of these isoforms, all but CYP2E1 play a prominent role in drug interactions important in the specialized field of dermatology. CYP1A2, 2B6, 2C9, 2C19, and 2D6 all have polymorphisms. Q3.3 Based on the percentage of drugs metabolized by the respective isoforms, CYP2C9, 2D6, and 3A4 are most important for drug metabolism (see Table 3.2 ).

CYP Polymorphisms

Q3.4 Many CYP isoforms show significant genetic polymorphism. Approximately 40% of human CYP-dependent drug metabolism is carried out by polymorphic CYP enzymes. This can translate into variable enzyme activity between individuals. Depending on the enzyme activity, individuals are designated as:

• 1.

  ‘Poor metabolizers’ (PM) if they have very low to no enzyme activity.

• 2.

  ‘Intermediate metabolizers’ (IM) if there is reduced activity.

• 3.

  ‘Normal metabolizer’ or ‘extensive metabolizer’ (NM/EM) if there is average enzyme activity with at least one functional allele.

• 4.

  ‘Ultrarapid metabolizers’ (UM) if there is exceptionally high enzyme activity.

This has important clinical relevance for medications that have a narrow therapeutic index. For example, if a clinician could predict how a patient would metabolize a specific medication, then the starting dose could be altered to avoid unwanted adverse effects (AE). In a PM, the starting dose would be lower than in an EM. However, if the patient was a UM, a clinician could more aggressively uptitrate a medication to reach a therapeutic level with a greater assurance that the patient could safely tolerate the more aggressive dosing.

Aside from the genetic variability of CYP isoforms, drug metabolism can be influenced by other medications, as well as physical factors. Medications can affect the various CYP isoforms by either inhibition or induction of enzyme activity, making an individual more susceptible to developing a cutaneous ADR.

Drug Inhibition or Induction of CYP Isoforms

Drug-induced inhibition of various CYP isoforms plays an important role in many ADR. Inhibition reduces the metabolizing effects of the affected cytochrome. In turn, CYP inhibition increases drug levels and toxicity. This can occur after just 1 to 2 doses of a medication, with maximal inhibition being observed once steady state is achieved. Inhibition is typically competitive; however, few drugs are noncompetitive inhibitors that result in CYP alteration, inactivation, or destruction.

Induction of a CYP isoform causes an increase in its metabolic activity by increasing either the enzyme amount or level of its activity resulting in reduced drug levels. This is a much slower (up to a week or more) process than CYP enzyme inhibition, because induction relies on synthesis of additional CYP enzyme. Once an inducing agent is removed, the duration of enzyme induction is dependent on the degradation of the newly formed enzyme.

General Issues

Proton pump inhibitors and numerous anticonvulsants are the primary substrates metabolized by the CYP2C19 isoform. This isoform comprises approximately 5% of all drug metabolism.

Specific Alleles of Importance

Q3.6 There are several allelic variants (CYP2C19∗2–8) that show no enzymatic activity, which translates into a PM phenotype. This phenotype is observed in 1% to 23% of persons, with Asians having the highest incidence, and African-Americans and Caucasians having the lowest ( Table 3.6 ). Detailed prevalence of some of the CYP2C19 genotypes may be seen later, where ∗2/∗2, ∗2/∗3, and ∗3/∗3 are the PM ( Table 3.7 ).

In addition to acting as a strong CYP3A4 inhibitor, ketoconazole inhibits the CYP2C19 isoform, although it is not a substrate of this isoform. This dual inhibition is important, given that many medications metabolized by the CYP2C19 isoform are also metabolized by CYP3A4.

General Issues

CYP2D6 shows significant pharmacogenetic variation (polymorphism) and is integral in the metabolism of numerous medications, especially psychiatric, narcotic, and cardiac medications. Q3.7 With over 90 documented allelic variants reported, CYP2D6 displays remarkable polymorphism, sometimes with whole gene duplication. Overall, 20% to 30% of drugs are metabolized through this pathway, with more than 50 drug substrates known (see Table 3.2 ). Because of these important issues, CYP2D6 has been extensively studied. In contrast to CYP2C9, CYP2D6 alleles that alter enzymatic activity are common. The enzymatic activity can vary up to 1000-fold between allele types. Clinically this translates to at least a 50-fold difference in drug doses tolerated between various individuals; this principle is illustrated by the wide dosing range of the CYP2D6 substrate doxepin and various β-blockers. Research has also gone into CYP2D6 and its effects on estrogen-responsive breast cancer treatment with tamoxifen, with conclusions still being contested as to clinical significance.