Pharmacogenetics

Frans D. Suyatna Department of Pharmacology Medical Faculty University of Indonesia

Pharmacogenetics

Unusual (idiosyncratic) drug response hereditary basis overdosage, allergic reaction inborn error of metabolism (eg. phenylketonuria) Drug metabolism - Rapid vs. Slow (acetylation) - Extensive (EM) vs. Poor Metabolizer (PM) (CYP polymorphisms)

Pharmacogenetics

Genotype Phenotype Modes of inheritance additive autosomal dominant, eg. hepatic porphyrias autosomal recessive, eg. slow acetylation of INH sex-linked (dominant & recessive) Monogenic (mendelian) Polygenic Ecogenetics, eg. G6PD deficiency Toxicogenetics

Genetic variation in pharmacokinetics

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Transport (absorption, plasma protein binding) Transducer mechanisms (receptors,enzyme induction/inhibition) Biotransformation Excretory mechanism (renal & biliary transport)

General approaches
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Clinical observations Family or twin studies Animal model Protein polymorphisms DNA polymorphisms

Pharmacogenetic polymorphism
= a monogenic trait that is caused by the presence in the same population of more than one allele at the same locus and more than one phenotype in regard to drug interaction with the organism. The frequency of the least common allele is at least 1%

Classification of human pharmacogenetic disorders

Classification of human pharmacogenetic disorders

Less enzyme or defective protein

1.

Succinylcholine apnea - neuromuscular blocking agent - metabolism: butyrylcholinesterase - atypical variant: succinylcholine sensitive Cynthiana variant: succinylcholine resistant

Acetylation polymorphism

Conjugation reaction in drug biotransformation Enzyme: N-acetyltransferase (liver, gut mucosa, etc) Isoniazid (INH) in tuberculosis therapy Slow vs. Rapid acetylators Slow acetylator isoniazid-induced neurotoxicity, bladder Ca, druginduced lupus erythematosus (INH, procainamide, hydralazine)

Drug-induced hemolysis (G-6-PD deficiency)

Drug-induced hemolysis (G-6-PD deficiency)

CYP polymorphisms (1)

Poor vs. Extensive metabolizers Clinical relevance ? - quantitative role of enzyme - presence of active metabolite - small therapeutic index - pharmacokinetic variability not related to genetic polymorphism (drug interaction, environmental, factor, disease) Individually dose adjusted

CYP polymorphisms (2)

PM adverse drug reaction > EM is associated with liver, GI, bronchogenic neoplasms PM is associated Parkinsonism

Increased resistance to drugs

Steroid hormone resistance Cystic fibrosis abnormal response to --adrenergic, cholinergic agents Downs syndrome Increased sensitivity to atropine, -adrenergic agents

Enzyme induction
Drugs Steroid cyt. P450 heme pool Alcohol heme synthesis

heme synthesis heme precursors porphyria

Gene defect //

Abnormal drug distribution

Binding of drug to plasma protein Thyroxine: albumin prealbumin thyroxine-binding globulin Hemochromatosis (autosomal recessive) Copper (Wilson disease, autosomal recessive) Ceruloplasmin (2-globulin) deficient

Disorders of unknown etiology

1. Malignant hyperthermia (autosomal dominant) - hypermetabolic state of skeletal muscle, tachycardia, arrythmias, very high fever (43C), muscular rigidity - during general anesthesia (halogenated inhalation anesthetic plus succinylcholine)

Disorders of unknown etiology

2. Halothane-induced hepatitis - dose-dependent dose-independent (genetically-based) CF3CHClBr CF3CHCl CF3COX X:last oxidative metabolite, suicide substrate for CYP 3. Corticosteroid induced glaucoma (autosomal recessive)

Disorders of unknown etiology

4. Chloramphenicol induced aplastic anemia - dose-dependent dose-independent bone marrow aplasia - oxamyl chloride intermediate binds CYP covalently