DOC PREVIEW
UIC PCOL 425 - PHARMACOGENETICS

This preview shows page 1-2-3 out of 8 pages.

Save
View full document
View full document
Premium Document
Do you want full access? Go Premium and unlock all 8 pages.
Access to all documents
Download any document
Ad free experience
View full document
Premium Document
Do you want full access? Go Premium and unlock all 8 pages.
Access to all documents
Download any document
Ad free experience
View full document
Premium Document
Do you want full access? Go Premium and unlock all 8 pages.
Access to all documents
Download any document
Ad free experience
Premium Document
Do you want full access? Go Premium and unlock all 8 pages.
Access to all documents
Download any document
Ad free experience

Unformatted text preview:

-1- PHARMACOGENETICS T. GUENTHNER Objectives: Understand some of the genetic factors involved in inter-patient variability in drug response. Learn some of the common pharmacogenetic polymorphisms. Appreciate the important role of drug metabolism in determining drug response. CASE STUDIES: Patient 1. A 69 year old woman was hospitalized for moderate to severe depression and treated with nortriptyline in a modest dose of 25 mg 3 times daily. Two days after the start of treatment she complained of dizziness. After a further 6 days of treatment, she complained of increasing tiredness and vertigo and appeared slightly confused. Low clearance of nortriptyline was suspected, blood was taken for nortriptyline analysis and the dosage was decreased to 25 mg once daily. The plasma concentration of nortriptyline after 8 days of treatment with the 75 mg daily dose was 1300 nM (recommended plasma concentration range 200-600 nM). The concentration on 25 mg daily for 12 days was 742 nM. When the dosage was further reduced to 20 mg at night, the patient had no side effects, and made an excellent recovery. Patient 2. A 41 year old woman had been treated for long periods with high doses of nortriptyline (300-500 mg /day) to achieve therapeutic plasma levels (200-600 nM). The mean (+s.d.) plasma level in seven samples drawn at a dose of 300 mg/day was 291 +/- 56 nm. The plasma concentration of unconjugated 10-hydroxynortriptyline was about 10 times higher than that of the parent drug, which is much higher than usual. Pharmacogenetics: originally defined as “..clinically important hereditary variation in response to drugs” (F. Vogel, 1959) 2 Sources of intrapatient variability in response to drugs: 1) Environmental - disease - other drugs or chemicals -inhibition at receptors - inhibition of drug metabolism and clearance -induction of drug metabolism - induction or “up-regulation” of receptors -usually results in a unimodal or “normal” distribution 2) Hereditary (or Pharmacogenetic) - receptors-2- - “disposition” factors, primarily metabolism - initially observed as bi- or tri- modal distribution (classic Mendelian model) Historical examples 1) Serum esterases Prolonged apnea following succinylcholine administration 2) G6P Dehydrogenase High incidence of hemolytic anemia among Afro-Caribbean males treated for malaria-3- with primaquine. Red cell lysis due to toxic oxygen species generated by primaquine metabolites. Susceptibility to anemia due to lack of protection by G6P dehydrogenase: X-linked recessive defect(s) in G6Pdh enzyme; especially prevalent among African and Mediterranean ethnic groups. 3) N-Acetyltransferase Peripheral neuropathy as side-effect of isoniazid treatment for tuberculosis. Due to defect(s) in N-acetyltransferase enzyme (“Slow acetylator” phenotype) Autosomal recessive trait whose prevalence varies widely among ethnic groups-4- Prevalence of “slow acetylator” phenotype in various gene pools: Ethiopian 90% European Caucasian 50% East/Central Asian 10%-20% Canadian Eskimo 5% More Recent Examples: 1) Thiopurine N-Methyl Transferase (TPNMT) Approximately 1 in 300 pediatric cancer patients treated with thiopurine drugs is at risk for life-threatening severe myelosuppression, due to complete lack of ability to methylate thiopurines Metabolic deficiency due to 2 Single Nucleotide Polymorphisms (SNPs) in open reading frame of TPNMT gene, resulting in inactive enzyme Additional variations in 5' flanking region (17 bp repeat element repeated 4 - 8 times); probably affects level of enzyme expression. Phenotype screening routinely done on rbc TPNMT activity; genotyping done as confirmatory followup.-5- 2) CYP2D6 First described as idiosyncratic adverse responses to debrisoquine, an antihypertensive drug not used in US; adverse responses included postural hypotension and dizziness. Variability reflected in variations in rates of debrisoquine hydroxylation, the major metabolic pathway for this drug. Distribution of “Poor Metabolizer” (PM) phenotype varies in different ethnic groups: 7%-10% among Caucasian Europeans <1% among East Asians CYP2D6 is the primary enzyme that hydroxylates debrisoquine; it also metabolizes many other prescription drugs (~ 1/4 of all known drugs)-6- Debrisoquine hydroxylase activity correlates with presence of variant alleles of CYP2D6 At least 20 variant CYP2D6 alleles exist; different variants predominate in different ethnic groups. Variants include SNPs in open reading frame causing frame shifts or aa substitutions, SNPs at exon junctions causing splice variants, gene deletion and multiple gene copies.-7- Extensive metabolizer” (EM) phenotype also exists; these people have duplicate or multiple copies of the CYP2D6 gene (2-12 copies), producing rapid metabolism (low MR - ratio of parent drug/metabolite) Percentage of EM phenotype also varies among ethnic groups: Northern Europeans (Sweden) 1%-2% Southern Europe (Spain, Sicily) 7% - 10% Northern Africa, Middle East (Ethiopia, Saudi Arabia) 20%-30% Variation in CYP2D6-dependent metabolic capacity can have major clinical implications. Rapid genotyping screens are being developed.-8- Polymorphisms for other CYP forms exist as well; Example - CYP2C19, responsible for metabolism of the commonly prescribed anticoagulant Warfarin. PM phenotype present in 3%-5% of Caucasians, 20% of ethnic Chinese. PM pts at risk for hemorrhage. Some pharmacogenetic variations are known for specific drug receptors. The number of therapeutically significant “receptor polymorphisms” appear to be much more limited than the number of therapeutically significant “drug metabolism polymorphisms” Examples: beta2 adrenoreceptor variants – differences in bronchodilation response Glycoprotein IIIa variants – decreased response to platelet aggregation inhibitors Cholesterylester transfer protein – enhanced response to pravastatin ACE – enhanced response to enalaprilate in mutant


View Full Document

UIC PCOL 425 - PHARMACOGENETICS

Documents in this Course
Exam 3

Exam 3

7 pages

Kozasa

Kozasa

14 pages

Load more
Download PHARMACOGENETICS
Our administrator received your request to download this document. We will send you the file to your email shortly.
Loading Unlocking...
Login

Join to view PHARMACOGENETICS and access 3M+ class-specific study document.

or
We will never post anything without your permission.
Don't have an account?
Sign Up

Join to view PHARMACOGENETICS 2 2 and access 3M+ class-specific study document.

or

By creating an account you agree to our Privacy Policy and Terms Of Use

Already a member?