Pharmacokinetics and Pharmacogene Variation

• This module aims to help learners understand the influence of pharmacogene variation on pharmacokinetics.
• Pharmacogene variation can impact a drug dosing regimen, including loading dose, maintenance dose, and dosing interval.
• Key CYP genes (CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A5) involved in phase 1 metabolism affect therapeutic drug response.
• Variable drug response is the observable phenotype, influenced by genes and environment like smoking, alcohol intake, age and disease
• The four basic processes involved in pharmacokinetics are adsorption, distribution, metabolism, and elimination.

Relationships between PGx and PK

• Variations in drug-metabolizing and transporter genes influence loading dose (DL), maintenance dose (DM), and drug dosing interval (Tau).
• Loading dose (LD) is the initial higher dose to achieve the desired drug concentration quickly.
• Maintenance dose (MD) is the regular amount taken to keep the drug concentration steady over time
• Dosing interval is how often the medication is taken
• Genetic variations can affect all of these and is caused by alteration in ADME
• Pharmacodynamic (PD) pharmacogenes encode drug receptors and drug targets.

Absorption and PGx

• The rate and extent (F) of absorption can be influenced by genetic variation.
• The absorption rate constant (ka) and the elimination rate constant (kel) determine tmax and Cmax.
• If kel is constant, changes in ka can affect tmax
• Genetic influences on transporters can affect ka and tmax for drugs that need to cross biologic membranes.
• Transporters at the apical membrane of enterocytes assist or reduce drug absorption.
• ABC transporters at the enterocyte's apical membrane limit drug absorption by effluxing the drug back into the intestinal lumen.
• Transporter function (uptake and efflux) affects the rate and extent of drug absorption, influencing systemic drug exposure.
• Genetic variation can alter the function of drug transporters, impacting absorption rate.
• If drug elimination is constant, ka impacts absorption rate and effects on tmax and Cmax

Distribution and PGx

• Volume of distribution (VD) relates the amount of drug in the body to the drug concentration.
• Drug distribution depends on physicochemical properties, physiology, and pathophysiology, and genetics can affect distribution.
• In tissues, influx (uptake) and efflux transporters are related not to absorption but to distribution.
• Alterations in drug distribution can affect efficacy and/or toxicity and genetic variation in SLCO1B1 leads to less active OATP1B1

Metabolism and PGx

• Small variations could have an impact on how people respond to drugs
• Drug metabolism in the liver affects the rate and extent of drug absorption and genetic variants
• Drugs entering enterocytes are metabolized by phase 1 (oxidation, reduction, hydrolysis) and phase 2 (acetylation, glucuronidation, sulfation) metabolizing enzymes.
• A given drug can be a substrate for multiple metabolizing enzymes.
• Drug metabolizing enzyme activity is defined relative to metabolizer phenotypes like UM, RM, NM, IM, PM.

Elements of Drug Disposition

• Phase one includes oxidation, reduction, and hydrolysis, which is mediated mostly by Cytochrome P450s
• Catalyzes reactions that unmask or insert polar functional groups
• Can lead to enhanced excretion and elimination
• Drug clearance and t1/2 are the PK parameters to watch for.

Biology of CYP450s

• Cytochrome P450s are a superfamily of oxidative enzymes.
• Over 50 human CYPs are clustered in 18 families.
• 6 CYPs (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5) metabolize 90% of all drugs and over 50% in the top 300.
• Function in Drug Metabolism is ~80% of phase I metabolism, hormones, arachidonic acid, cholesterol and detoxification.
• Genetic polymorphisms in CYPs lead to clinical consequences.

CYP2C Genes

• CYP2C8, CYP2C9, CYP2C18, CYP2C19 are clustered with 4 genes.
• Located on chromosome 10q23.33
• All 4 genes have 9 exons in their coding regions
• Polymorphisms in the coding regions are linked with metablizer phenotypes
• CYP2C9 is a key player in warfarin metabolism, so dose matters as it has a narrow therapeutic window.
• Argining changes to cystemine in people, w/ #2

Summary of CYP2C9 Polymorphisms in Phenotypes

• Only normal and intermediate metabolizers are deduced
• Extensive (Normal) Metabolizers (EMs) are Homozygotes for the wild type CYP2C9*1 allele (*1/*1)
• Intermediate Metabolizers (IMS) are Heterozygotes of reduced function alleles
• Poor Metabolizers (PMs) are Homozygotes of reduced function alleles

Clinical Relevance of CYP2C9 Pharmacogenomics

• Warfarin normal starting dose should be ~ 5 mg
• Individuals are classified as either sensitive or resistant based on starting doses.
• Forty percent of variability in initial warfarin dose is attributed to genetics
• VKORC1 in particular accounts for 25%, CYP2C9 accounts for 12%.

Ethnic Differences in PGx of Warfarin PK

• ~30% reduction in enzyme activity is CYP2C9*2
• ~70-95% reduction in enzyme activity in CYP2C9*3

Public Health considerations

• Genotype before initiation of warfarin therapy
• Normal dosing for warfarin is 5mg,
• A chart includes Three Ranges of Expected Maintenance COUMADIN Daily Doses Based on CYP2C9 and VKORC1 Genotypes

CYP2C19

• CYP2C19 Relevant Polymorphisms,
• 1-wild type
• alternate splice mutation in eon 5 There 4 SNPs account for the majority

Phenotypic Summary of CYP2C19 Polymorphisms

• Rapid metabolizers break down drugs very fast, to a point where it's not enough
• Ploor functionality causes average amounts to build up and cause side effects

PGx of CYP2C19

• Clopidogrel is a thienopyridine antiplatelet prodrug indicated for the prevention of atherothrombotic events, but requires activiation of CYP2C19
• Active metabolites inhibits ADP ○PMs - increased risk of adverse cardiovascular events ○UMs - increased risk of bleeding

Recommended Phenotypes CYP2D6

• Highly polymorphic, due to 160 allles
• Fully functional alleles *1 and *2
• PM cannot break it down increased ADE and a 50% decrease is recommended from normal dose
• UM has a decreased affect and recommend to increase dosage by 1.5 to 2x from normal dose

Clinical relevance of CYP2D6

• Various tests for CYP2D6 genotype exist, and has rececently be apprived by FDA 10 is highly sigficcant in affect on the the brain.

Explore the influence of pharmacogene variation on pharmacokinetics, focusing on drug dosing regimens (loading dose, maintenance dose, and dosing interval). Key CYP genes and their impact on therapeutic drug response are discussed. Variable drug response, influenced by genes and environment, alongside the four basic processes of pharmacokinetics (adsorption, distribution, metabolism, and elimination) are key.