Pharmacogenomics and Pharmacokinetics ^

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1 Pharmacogenomics and Pharmacokinetics ^ avid F. Kisor, B.S., Pharm.. Profeor of Pharmacokinetics epartment of Pharmaceutical and Biomedical Sciences Raabe College of Pharmacy Ohio Northern University Learning Objectives Pharmacists ifferentiate the major types of genetic variation, including nonsynonymous, synonymous, and insertions/deletions (indels) as a consequence of single nucleotide polymorphisms (SNPs). Indentify how specific genetic polymorphisms influence drug absorption, distribution, metabolism and excretion. Explain how a specific SNP would affect the design of a patient s drug dosing regimen. Recognize the influence of genetics and specific SNPs on the use of specific drugs, including abacavir, carbamazepine, clopidogrel, 5-Fluorouracil, irinotecan, 6-Mercaptopurine, and warfarin. Pharmacy Technicians Recognize how NA variation can affect a person s response to a drug. 2 Pharmacogenomics vs. Pharmacogenetics Pharmacogenomics (PGx) refers to how all of the genes (the genome) can influence responses to drugs. Pharmacogenetics (PGt) refers to how variation in one single gene influences the response to a single drug. The Basis for Genetic Variability Related to rug Response NA Nucleotide Bases The triphosphates of the purines: Adenine (A), Guanine (G), and pyrimidines: Cytosine (C) and Thymine (T) Source: Pharmacogenomics Knowledgebase. Acceed 2/25/2013. Food and rug Administration. Acceed 2/25/ NA to Protein rug Targets Common Nucleotide Sequence: Common Amino Acid Sequence: Tyr- 5 NA to Protein rug Targets Common Nucleotide Sequence: 6 1

2 NA to Protein rug Targets Common Nucleotide Sequence: Leu- 7 NA to Protein rug Targets Common Nucleotide Sequence: Leu- Glu- 8 NA to Protein rug Targets Common Nucleotide Sequence: Leu- Glu- Phe- 9 NA to Protein rug Targets Common Nucleotide Sequence: Leu- Glu- Phe- Gly- 10 NA to Protein rug Targets Common Nucleotide Sequence: Leu- Glu- Phe- Gly- Val- 11 NA to Protein rug Targets : s Receptors or Transporters or Enzymes Examples: Histamine β-adrenergic Sources: drugsandgenes.com, Leja,. Enzyme. National Human Genome Research Institute. Examples: CYP26 TPMT Examples: P-glycoprotein OATP1B1 12 2

3 TAC AAG CTG GAG TTC GGT GTC 13 NA to Protein rug Targets Variant Nucleotide Sequence: TAC AAG CTG GAG TTC GGT GTC Leu- Glu- 14 TAC AAG CTG GAG TTC GGT GTC TAC AAG CTG GAC TTC GGT GTC SNP synonymous change (sense) NA to Protein rug Targets Variant Nucleotide Sequence: TAC AAG CTG GAG TTC GGT GTC Leu- Asp- 17 TAC AAG CTG GAC TTC GGT GTC Tyr-Lys-Leu-Asp-Phe-Gly-Val SNP nonsynonymous change (nonsense) Abnormal function protein 18 3

4 TAG AAG CTG GAC TTC GGT GTC 19 NA to Protein rug Targets Variant Nucleotide Sequence: TAG AAG CTG GAC TTC GGT GTC Common Amino Acid Sequence: Stop 20 Common Nucleotide Sequence: TAG AAG CTG GAC TTC GGT GTC TAC AAG CTG CGA ATT CGG TGT C stop Abnormal function protein SNP stop change (miense) NA to Protein rug Targets Variant Nucleotide Sequence: TAC AAG CTG CGA ATT CGG TGT C Leu- Arg- Ile- Arg- Cys- 23 Common Nucleotide Sequence: TAC AAG CTG CGA ATT CGG TGT C Tyr-Lys-Leu-Arg-Ile-Arg-Cys SNP insertion Abnormal function protein 24 4

5 Common Nucleotide Sequence: Common Amino Acid Sequence: TAC AAG CTG AAT TCG GTG TC 25 NA to Protein rug Targets Variant Nucleotide Sequence: TAC AAG CTG _AAT TCG GTG TC Leu- Arg- Asn- Ser- Val- 26 Common Nucleotide Sequence: Common Amino Acid Sequence: TAC AAG CTG AAT TCG GTG TC Examples CYP2C19 CYP26 Gene SNP Type Consequence SLCO1B1 c.681g>a rs delA rs c.521t>c rs Synonymous* Lo-of-function eletion Lo-of-function Nonsynonymous * although synonymous, protein function is lost Reduced activity Tyr-Lys-Leu-Asn-Ser-Val Abnormal function protein SNP deletion Occur approximately once every 300 bases Result in: no change in protein function decreased protein function lo of protein function increased protein function Can alter: pharmacokinetics (via transporters and enzymes) absorption, distribution, metabolism, excretion pharmacodynamics (via receptors) Gastrointestinal Absorption Mechanisms paive diffusion facilitated diffusion pinocytosis ionic diffusion active transport polymorphic influx (uptake) transporters efflux transporters

6 Gastrointestinal Absorption - Bioavailability Gastrointestinal Absorption influx (uptake) transporters efflux transporters Transporter Type Substrates OATP influx enalapril PEPT1 influx ampicillin normal expreion of an efflux transporter overexpreion of an efflux transporter* F ose * C = CL τ P-glycoprotein efflux lansoprazole BCRP efflux methotrexate Example: SNP causing overexpreion of P-glycoprotein Source: Kisor F, Kane M, Talbot JN, Sprague JE. Pharmacogenetics, Kinetics, and ynamics for Personalized Medicine. JB Learning Gastrointestinal Metabolism Cytochrome P-450 enzymes Enzyme CYP26 CYP2C9 CYP2C19 CYP3A Substrates codeine warfarin clopidogrel carbamazepine Gastrointestinal Metabolism CYP2C9 14% CYP2C19 2% CYP2J2 1% CYP3A 82% CYP26 1% Percent Contribution Adapted from: Paine MF, Hart HL, Ludington SS, Haining RL, Rettie AE, Zeldin C. rug Met isp Gastrointestinal Metabolism - Bioavailability Gastrointestinal Absorption and Metabolism * F ose * C = CL τ C = F ose CL τ Increased gastrointestinal wall efflux = Bioavailability Example: SNP causing lo-of-function CYP26 Source: Kisor F, Kane M, Talbot JN, Sprague JE. Pharmacogenetics, Kinetics, and ynamics for Personalized Medicine. JB Learning ecreased gastrointestinal wall metabolism = Bioavailability

7 istribution Blood = drug IT = Influx transporter Cells / Tiue istribution - SNP overproduction of an influx transporter Blood = drug IT = Influx transporter Cells / Tiue Vd t½ = CL istribution - SNP overproduction of an influx transporter Blood = drug E = enzyme M = metabolite IT = Influx transporter Hepatocyte E M E M E M E M E M Increased Vd; E M Increased CL istribution - SNP underproduction of an influx transporter Blood = drug E = enzyme M = metabolite IT = Influx transporter Hepatocyte E M ecreased Vd; ecreased CL rug Metabolism Metabolism phenotype Normal metabolism = extensive metabolizer (EM) Intermediate metabolizer (IM) Poor metabolizer (PM) Ultrarapid metabolizer (UM) Hepatic Metabolism CYP2A6 6% CYP2E1 9% CYP26 2% CYP2B6 <1% CYP3A4/5 40% CYP1A2 18% CYP2C 25% Percent Contribution Adapted from: Shimada T, et al. J Pharmacol Exp Ther. 270: ,

8 rug Metabolism Metabolism phenotype PM rug Metabolism CYP219 Allele 1 CYP2C19 Allele 2 *17 *17 SNP c.-806c>t rs Metabolic Phenotype UM *1 *1 - EM IM *1 *2 c.681g>a rs IM EM *2 *2 c.681g>a rs PM UM *2 *3 c.681g>a rs c.636g>a rs PM rug Metabolism UM; C F ose = ; CL τ M = CL C rug Excretion Renal EM;C F ose = ; CL τ M = CL C F ose IM; C = ; M = CL C CL τ F ose PM; C = ; M = CL C CL τ Biliary Source: Kisor F, Kane M, Talbot JN, Sprague JE. Pharmacogenetics, Kinetics, and ynamics for Personalized Medicine. JB Learning rug Labels and Pharmacogenomics Over 100 drugs with pharmacogenomic information in the label. 17 fall in the list of the 200 most commonly prescribed drugs of fall in the top 10 with more than 68 million prescriptions written in Mercaptopurine rug target: Enzyme Thiopurine Methyl Transferase (TPMT) SNP rs# Consequence *2 G>C rs# Lo of TPMT activity *3A A>G and G>A rs# and rs# Lo of TPMT activity *3C A>G rs# Lo of TPMT activity *4 G>A rs# Lo of TPMT activity Heterozygous, e.g. *1/*3A: Reduce ose to 30-70% of full dose Homozygous, e.g. *2/*2: Reduce by 10-fold

9 Warfarin rug targets: Metabolizing Enzyme CYP2C9 Enzyme activating vitamin K - VKORC1 CYP2C9 SNP rs# Consequence *2 C>T rs# Reduced CYP2C9 function *3 A>C rs# Reduced CYP2C9 function VKORC1 *2 H G>A rs# Increased sensitivity to warfarin Clopidogrel rug target: Metabolizing Enzyme CYP2C19 SNP rs# Consequence *2 G>A rs# Lo of CYP2C19 function *17 C>T rs# Increased CYP2C19 function Clopidogrel rug target: Metabolizing Enzyme CYP2C19 Clopidogrel SNP rs# Consequence *2 G>A rs# Lo of CYP2C19 function *17 C>T rs# Increased CYP2C19 function Initiate antiplatelet therapy with prasugrel or other Clopidogrel Pharmacogenomics and Pharmacokinetics Thank you! Questions? Michael. Kane, Jeffery N. Talbot, Jon E. Sprague CPIC OSHP