Pharmacogenetics and Pharmacoepidemiology “PHCY 480” University of Nizwa College of Pharmacy and Nursing School of Pharmacy Pharmacogenetics and Pharmacoepidemiology “PHCY 480” Lecture 5 Drug metabolism

Allele Alleles are different forms of the same gene. Most organisms have two sets of chromosomes. Alleles are always found on the same loci (position) of two homologous chromosomes. e.g. the height of individuals is often divided into two traits tall T and short t. Tall is one allele and short is another of the height trait.

Allele Homozygous This is seen in the genotype of the individual. It happens when two identical genes are found in the same loci of two homologous chromosomes. e.g. for the height characteristic homozygous would be seen as TT or tt Heterozygous This is also seen in the genotype of the individual. It happens when two different genes are found in the same loci of two homologous chromosomes. e.g. for the height characteristic homozygous would be seen as Tt

Allele

Drug Metabolizers The drug is metabolized by CYP450 enzyme. A person can metabolize a probe drug slower than others. In that case, person can be a poor metabolizer (PM) of one probe drug, and an extensive metabolizer (EM) of another. Four types of metabolizers: Extensive metabolizers (EM) Poor metabolizers (PM) Ultra-extensive metabolizers (UM) Intermediate metabolizers (IM)

Extensive metabolizers (EM) Genotypes consistent with EM phenotype include two active forms of the gene producing the drug metabolizing enzyme They posses the full complement of drug metabolizing capacity. EM may require standard dosage due to standard rate of drug metabolism.

Poor metabolizers (PM) Genotypes consistent with the PM phenotype are those with no active genes producing the drug metabolizing enzyme. These individuals have a deficiency in drug metabolism. PM are at increased risk of drug-induced side effects due to diminished drug elimination or lack of therapeutic effect resulting from failure to generate the active form of the drug.

Ultra-extensive metabolizers (UM) Genotypes consistent with UM phenotype include three or more active genes producing the drug metabolizing enzyme. They have increased metabolic capacity. UM may require an increased dosage due to higher than normal rates of drug metabolism.

Intermediate metabolizers (IM) IM may require lower than average drug dosages for optimal therapeutic response.

Polymorphic P- 450s Many commonly prescribed drugs are metabolized by enzymes with polymorphic alleles. CYP2C9: CYP2C9 is located on chromosome 10, and is polymorphic in 1-3% of Caucasians.

Polymorphic P- 450s CYP2C19: CYP2C19 is located on chromosome 10, and is polymorphic in: 2-4% of African-Americans 3-5% of Caucasians 15-20% of Asians

Polymorphic P- 450s CYP2D6: Located on chromosome 22, and is polymorphic in 5-10% of Caucasians.

Polymorphic P- 450s Polymorphic CYP-450 Genes and Poor Metabolizers: Prodrug: If the drug is a prodrug, metabolism is required for activation. The prodrug may have poor efficacy, and possibly even accumulate in its inactive form in patients with a poor metabolizer phenotype. Active drug: If the drug is already an active drug and metabolism is required to inactivate the drug, a patient with a poor metabolizer phenotype will usually show good efficacy, but the inactive drug may accumulate and produce adverse reactions. Here, we should use lower doses of the drug.

Polymorphic P- 450s Polymorphic P-450 Genes and Poor Metabolizers:

Polymorphic P- 450s Ultra-rapid metabolizer phenotype: Prodrug: If the drug is a prodrug, it will be metabolized efficiently, and the active metabolite will have better efficacy and a more rapid onset of effect. Active drug: If the drug is already an active drug and metabolism is required to inactivate the drug, a patient with an ultra-rapid metabolizer phenotype may exhibit poor efficacy at standard doses in ultra-rapid metabolizers.

Polymorphic P- 450s Polymorphic P-450 Genes and Ultra-Rapid Metabolizers:

Polymorphic P- 450s Conjugates: In addition to Phase I reactions, such as those accomplished by CYP450, some drugs and metabolites are covalently linked together with another organic compound to create a conjugate (Phase II drug metabolism reactions). Generally, conjugated metabolites are less lipid soluble and more water soluble, thus facilitating renal excretion. Many conjugated metabolites are organic acids, and thus are also candidates for renal secretion. Conjugates are pharmacologically inactive (With few exceptions, such as morphine), so this pathway reduces drug activity.

Phase1, 2 and Conjugation Reactions Drug Derivative Conjugate Oxidation Hydroxylation Hydrolysis Conjugation Example Glucoronic acid Salicylic acid Glucoronide

Mechanisms of drug action Common Signalling mechanisms: Transmembrane enzymes, including tyrosine protein kinases Ligand gated ion channels G protein coupled receptors (i.e. epinephrine; neurotransmitters; glycoproteins; and thrombin) Intracellular response elements; transcription factors Example1 : Ligand gated ion channels. Binding of the neurotransmitter to these receptors can directly affects ion channel permeability.

Polymorphic P- 450s Polymorphic Examples: Some drug receptors and transporters that exhibit polymorphisms may affect clinical response.