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IMAS. Institut. Municipal. d’Investigació Mèdica. . IMIM.  Pharmacogenetic and Pharmacogenomic Aspects of Drug Abuse . Rafael de la Torre, PharmD, PhD Unitat de Recerca en Farmacologia. Institut Municipal d’Investigació Mèdica (IMIM). CEXS, Universitat Pompeu Fabra, Barcelona).

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pharmacogenetic and pharmacogenomic aspects of drug abuse

IMAS

Institut

Municipal

d’Investigació Mèdica

. IMIM

 Pharmacogenetic and Pharmacogenomic Aspects of Drug Abuse 

Rafael de la Torre, PharmD, PhD

Unitat de Recerca en Farmacologia.

Institut Municipal d’Investigació Mèdica (IMIM).

CEXS, Universitat Pompeu Fabra, Barcelona)

International Workshop on Pharmacogenomics and Pharmacogenetics: Current Challenges and Bioinformatics SupportBarcelona, 11-12 July, 2005

contribution of genetics to multifactorial diseases
Contribution of genetics to multifactorial diseases
  • Debate about the introduction THC in therapeutics and risk factors associated to its use (seminar). Among them there is an increased risk for developing schizophrenia in predisposed subjects.
  • In a Toxicology examination at UPF School of Biology, students were requested to discuss these risk factors. Some students wrote:
    • Candidate patients should be genotyped for schizophrenia meaningless
    • A psychiatric exploration would be more meaningful

International Workshop on Pharmacogenomics and Pharmacogenetics: Current Challenges and Bioinformatics SupportBarcelona, 11-12 July, 2005

slide3

(25-50%)

• DNA

• SNPs

• other polymorphisms

metabolism

neuroadaptation

withdrawal

(very high)

(very high)

(very high)

Factors Contributing to Vulnerability to Develop a Specific Addiction

International Workshop on Pharmacogenomics and Pharmacogenetics: Current Challenges and Bioinformatics SupportBarcelona, 11-12 July, 2005

J Pollock-NIDA (modified)

slide4

Social Phobias

Social Phobias

Alcohol and

Alcohol and

13

13

13

20

20

20

20

Alcohol and

Alcohol and

Years

Years

Years

Years

Drug Use

Drug Use

Panic Disorder

Panic Disorder

Drug Use

Drug Use

Disorders

Disorders

Disorders

Disorders

Bipolar Disorder

Bipolar Disorder

Age

Age

Age

Age

Age

Age

Age

Age

Age

Age

Age

Age

Age

Age

Eating Disorders

10

10

10

10

13

13

13

13

Years

Years

Years

Years

Obsessive Compulsive Disorders

-

-

-

Anti

-

social Behavior

-

-

-

5

5

5

5

10

10

10

10

Conduct Disorder

Brain

Brain

Brain

Brain

Years

Years

Years

Years

Depression

Disorders

Disorders

Disorders

Disorders

Anxiety

Infancy to

Infancy to

Infancy to

Infancy to

Attention Deficit Hyperactivity Disorder

5 Years

5 Years

5 Years

5 Years

Autism

Age of Onset of Brain Disorders

The link between schizophrenia

and cannabis consumption seems

to be strongly associated to the

age of first consumption (i.e. >15y

vs. <15y)

International Workshop on Pharmacogenomics and Pharmacogenetics: Current Challenges and Bioinformatics SupportBarcelona, 11-12 July, 2005

slide5

Drug Addiction: A Developmental Perspective

metabolism

neuroadaptation

withdrawal

International Workshop on Pharmacogenomics and Pharmacogenetics: Current Challenges and Bioinformatics SupportBarcelona, 11-12 July, 2005

why we are concerned about genes in the context of drug addiction
Why we are concerned about genes in the context of drug addiction?
  • Better understanding of environmental factors in addiction
  • Will improve treatment interventions
  • Facilitate understanding the neurobiology of addiction and drug abuse

International Workshop on Pharmacogenomics and Pharmacogenetics: Current Challenges and Bioinformatics SupportBarcelona, 11-12 July, 2005

slide7

Substance abuse vulnerability loci: converging genome scanning data

  • There are 15 reproducible chromosomal loci identified,
  • good candidates to harbor allelic variants that alter
  • human substance abuse vulnerabilities.

Polygenic inheritance for

substance abuse vulnerability

Knowledge of genotypes at loci

containing vulnerability alleles

could improve the management

of vulnerable individuals and

thus the cost-effectiveness of

addiction prevention and

treatment

International Workshop on Pharmacogenomics and Pharmacogenetics: Current Challenges and Bioinformatics SupportBarcelona, 11-12 July, 2005

Uhl GR, TRENDS in Genetics 2002; 18:420-5

genes canditates associated with addictive diseases
Genes Canditates Associated with Addictive Diseases

International Workshop on Pharmacogenomics and Pharmacogenetics: Current Challenges and Bioinformatics SupportBarcelona, 11-12 July, 2005

orpm1 gene
ORPM1 gene

Ikeda K Trends Pharmacol Sci. 2005;26:311-7.

International Workshop on Pharmacogenomics and Pharmacogenetics: Current Challenges and Bioinformatics SupportBarcelona, 11-12 July, 2005

orpm1 gene and the a118g variant i
ORPM1 gene and the A118G variant (I)
  • >100 polymorphisms in humans
  • More abundant in the non-protein-coding regions
  • 10 SNPs in ORPM1 translated region
  • The A118G variant is the most frequent coding region variant in most samples
    • 45% in Asians
    • 5-25% in European and African-American
  • The A118G variant is a missense SNP that changes the N-terminal region amino acid (Asn40Asp)decrease in the number of sites for N-linked glycosilation of the MOP receptor from 5 to 4.
  • The A118G SNP increases three folds the affinity of b-endorphin for MOR

International Workshop on Pharmacogenomics and Pharmacogenetics: Current Challenges and Bioinformatics SupportBarcelona, 11-12 July, 2005

orpm1 gene and the a118g variant ii
ORPM1 gene and the A118G variant (II)
  • Associated to vulnerability to dependence on addictive substances
    • Opiates
    • Alcohol
    • Poly-drug use
  • Decreased sensitivity to major active morphine metabolite after its p.o. administration morphine-6-O-glucuronide
  • Alteration to stressors of the HPA axis

International Workshop on Pharmacogenomics and Pharmacogenetics: Current Challenges and Bioinformatics SupportBarcelona, 11-12 July, 2005

orpm1 gene and the a118g variant iii vulnerability to dependence on opiates and alcohol
ORPM1 gene and the A118G variant (III) Vulnerability to Dependence on Opiates and Alcohol
  • Study in a Swedish population (little admixture over the past centuries)
  • Allelic frequency of the 118G allele 11%
  • Opiates
    • 120 control subjects vs. 67 opiate dependent subjects
    • Association between the 118G allele and genotype and heroin addiction (OR=2.72, p=0.0025 and OR=2.97, p=0.0031)
    • Attributable risk due to genotypes with a G allele was 21.0% (95% CI 6.0-34.0%)
  • Alcohol
    • 120 control subjects vs. 193 alcohol dependent subjects
    • Association between the 118G allele and genotype and heroin addiction (OR=1.92, p=0.0074 and p=0.095)
    • Attributable risk due to genotypes with a G allele was 11.1% (95% CI 3.6-18.0%)

Bart G. Mol Psychiatry 2004;9: 547-9

and Neuropharmacology 2005;30:417-22

International Workshop on Pharmacogenomics and Pharmacogenetics: Current Challenges and Bioinformatics SupportBarcelona, 11-12 July, 2005

orpm1 gene and the a118g variant iv nicotine replacement therapy nrt
ORPM1 gene and the A118G variant (IV) Nicotine Replacement Therapy (NRT)
  • Rationale:
    • beta-endorphin is released following acute and short-term nicotine exposure
    • The mu-opiod receptor (OPRM1) related to reward effects of beta-endorphin
    • The Asp40 variant (A118G) increases binding affinity for beta-endorphin, and is found in 25-30% of subjects with European ancestry
  • Which is the clinical response to NRT as a function of the Asp40 variant?
    • Two treatments compared: transdermal nicotine (TN) vs. nicotine nasal spray (NS)
    • Population of 320 smokers (TN=153, NS=167), genotyped for the A118G

International Workshop on Pharmacogenomics and Pharmacogenetics: Current Challenges and Bioinformatics SupportBarcelona, 11-12 July, 2005

orpm1 gene and the a118g variant iv nicotine replacement therapy nrt1
ORPM1 gene and the A118G variant (IV) Nicotine Replacement Therapy (NRT)
  • Results:
    • Smokers carrying the Asp40 variant when compared to homozygous for Asn40 were more likely
      • to be abstinent at the end of treatment (52%vs.33%),
      • to report less mood disturbances
      • to gain less weight (0.7vs.2.1 kg)
    • Effects more pronounced on subjects treated with the high dose of TN
    • Differences between genotype equivalent to comparison of placebo vs. NRT

Lerman C Pharmacogenomics J. 2004;4:184-192

International Workshop on Pharmacogenomics and Pharmacogenetics: Current Challenges and Bioinformatics SupportBarcelona, 11-12 July, 2005

orpm1 gene and the a118g variant iv naltrexone ntx and alcoholism
ORPM1 gene and the A118G variant (IV) Naltrexone (NTX) and Alcoholism
  • Rationale:
    • beta-endorphin compensation model alcoholics have a relative deficiency in endogenous opioids when confronted with stressful situations.
    • Alcohol increase endogenous opioids and this may account for its reinforcing properties
    • The Asp40 variant (A118G) increases binding affinity for beta-endorphin, and is found in 25-30% of subjects with European ancestry
  • Which is the clinical response to naltrexone as a function of the Asp40 variant?
    • Two treatments compared: NTX vs. placebo
    • Population of 82 patients treated with NTX vs. 59 treated with placebo

International Workshop on Pharmacogenomics and Pharmacogenetics: Current Challenges and Bioinformatics SupportBarcelona, 11-12 July, 2005

orpm1 gene and the a118g variant iv naltrexone ntx and alcoholism1
ORPM1 gene and the A118G variant (IV) Naltrexone (NTX) and Alcoholism
  • Results:
    • Alcoholics treated with NTX carrying the Asp40 variant when compared to homozygous for Asn40 had lower rates of relapse (p=0.04) and longer time to return to heavy drinking
    • Patients homozygous for Asn40 treated with NTX were not different from placebo

Oslin DW Neuropsychopharmacology

2003;28:1546-52

International Workshop on Pharmacogenomics and Pharmacogenetics: Current Challenges and Bioinformatics SupportBarcelona, 11-12 July, 2005

potential role of pharmacogenetics of cyp enzymes in drug abuse dependence and neurotoxicity
Potential role of pharmacogenetics of CYP enzymes in drug abuse, dependence and neurotoxicity
  • The CYP superfamily of heme-based oxidases are genetically variable and are involved in the metabolic detoxification / activation of a number of drugs of abuse
  • Hypothesis: differences in pattern of drug metabolism among individuals and across ethnic groups due to genetic variability are likely to affect the risk of drug dependence and neurotoxicity
    • The effects of genetically variable metabolism on drug dependence depends on whether the parent drug, metabolite(s) or both are responsible for its addictive properties
    • The effects of genetically variable metabolism on neurotoxicity depends on the fraction of the drug bioactivated to neurotoxic species

International Workshop on Pharmacogenomics and Pharmacogenetics: Current Challenges and Bioinformatics SupportBarcelona, 11-12 July, 2005

potential role of pharmacogenetics of cyp enzymes in drug abuse and dependence
Potential role of pharmacogenetics of CYP enzymes in drug abuse and dependence
  • Non functional allelic variants or allelic variants associated with enzymes with low activity might be associated with an increased drug abuse liability or alternatively might protect against drug dependence
    • CYP2D6 (codeine, methamphetamine)
    • CYP2A6 (nicotine)

International Workshop on Pharmacogenomics and Pharmacogenetics: Current Challenges and Bioinformatics SupportBarcelona, 11-12 July, 2005

cyp2d6 and drug abuse liability

In subjects with functional

alleles

Higher drug abuse liability

Higher analgesic effects

In subjects with non-functional

alleles

Higher drug abuse liability

CYP2D6 and drug abuse liability

International Workshop on Pharmacogenomics and Pharmacogenetics: Current Challenges and Bioinformatics SupportBarcelona, 11-12 July, 2005

cyp2a6 and nicotine dependence
CYP2A6 and nicotine dependence

No CYP2A6 activity, Homozygous for CYP2A6*2, CYP2A6*4, and CYP2A6*5 inactive alleles;

50% CYP2A6 activity, heterozygous for inactive alleles and homozygous for any combination of reduced activity alleles CYP2A6*6, CYP2A6*7, CYP2A6*9, CYP2A6*10, and CYP2A6*12;

75% CYP2A6 activity, heterozygous for reduced activity alleles;

Normal (100%) CYP2A6 activity, remaining percentage of those not included in any other group.

International Workshop on Pharmacogenomics and Pharmacogenetics: Current Challenges and Bioinformatics SupportBarcelona, 11-12 July, 2005

Malaiyadi V, CPT, 2005,77, 145-58

cyp2a6 and nicotine dependence1
CYP2A6 and nicotine dependence
  • Hypothesis: Slow inactivators of nicotine
    • Reduced risk for smoking
    • Lower amount smoked
    • Altered smoking intensity (first smoking)
    • Increased quitting
    • Lower risk of lung cancer (inhibition of pro-carcinogens bioactivation)

Some conflicting results, but several experimental

studies support the hypothesis

CYP2A6 phenocopying as a novel approach for

smoking reduction and cessation

International Workshop on Pharmacogenomics and Pharmacogenetics: Current Challenges and Bioinformatics SupportBarcelona, 11-12 July, 2005

potential role of pharmacogenetics of cyp enzymes in drug abuse toxicity and neurotoxicity

Potential role of pharmacogenetics of CYP enzymes in drug abuse toxicity and neurotoxicity

MDMA AND PHARMACOGENETICS

International Workshop on Pharmacogenomics and Pharmacogenetics: Current Challenges and Bioinformatics SupportBarcelona, 11-12 July, 2005

mdma and pharmacogenetics
MDMA and pharmacogenetics
  • Do genetic polymorphism in enzymes involved in MDMA metabolic disposition contribute to any extend to acute toxic effects?
  • In females of Dark Agouti rats, deficient in the CYP2D1 isozyme a drastic reduction of the rate of O-demethylenation of MDMA when compared to SD rats was observed.

CYP2D6

MDMA

  • In yeast microsomes expressing human CYP2D6, it was demonstrated that this isozyme regulated partially the O-demethylenation of MDMA. At high MDMA concentrations other isozymes of cytochrome P450, CYP1A2, CYP3A4, CYP2B6 contribute to this metabolic reaction

HHMA

International Workshop on Pharmacogenomics and Pharmacogenetics: Current Challenges and Bioinformatics SupportBarcelona, 11-12 July, 2005

mdma pharmacogenetics and acute toxicity i
MDMA pharmacogenetics and acute toxicity (i)
  • CYP2D6 is a polymorphic enzyme in humans with several allelic variants some of them leading to non-functional or partially functional enzymes.
  • Several phenotypes are present in the population: extensive(homozygous for functional alleles), intermediate (homozygous partially functional or heterozygous for a non-functional allele), poor (homozygous for non functional alleles) and ultrarapid (gene duplication of functional alleles) metabolizers.
  • The fact that O-demethylenation of MDMA is regulated partially by CYP2D6 immediately raised the question: To which extend poor metabolizers (PM) are at higher risk of acute toxicity episodes?

International Workshop on Pharmacogenomics and Pharmacogenetics: Current Challenges and Bioinformatics SupportBarcelona, 11-12 July, 2005

mdma pharmacogenetics and acute toxicity ii
MDMA pharmacogenetics and acute toxicity (ii)
  • This risk has never been confirmed in humans after CYP2D6 genotyping of MDMA casualties. No bias towards PM subjects has been observed
  • The fact that O-demethylenation of MDMA is regulated partially by CYP2D6 immediately raised the question: To which extend poor metabolisers (PM) are at higher risk of acute toxicity episodes?

Why?

International Workshop on Pharmacogenomics and Pharmacogenetics: Current Challenges and Bioinformatics SupportBarcelona, 11-12 July, 2005

mdma metabolic disposition in humans
MDMA metabolic disposition in humans

MDMA

CYP2D6

HHMA

COMT

HMMA

International Workshop on Pharmacogenomics and Pharmacogenetics: Current Challenges and Bioinformatics SupportBarcelona, 11-12 July, 2005

slide27

MDMA INHIBITS ITS OWN METABOLISM

Amounts of CYP2D6 in liver

are limited and easily saturated

Metabolites formation at doses

higher than 75 mg is regulated

by the dissociation of the carbene

complex and independent of the

dose

International Workshop on Pharmacogenomics and Pharmacogenetics: Current Challenges and Bioinformatics SupportBarcelona, 11-12 July, 2005

slide28

HMMA

MDMA

MDMA NON-LINEAR PHARMACOKINETICS

MDMA 50 mg

MDMA 150 mg

MDMA 100 mg

International Workshop on Pharmacogenomics and Pharmacogenetics: Current Challenges and Bioinformatics SupportBarcelona, 11-12 July, 2005

slide29

MDMA NON-LINEAR PHARMACOKINETICS

Summary

PLASMA

URINE

International Workshop on Pharmacogenomics and Pharmacogenetics: Current Challenges and Bioinformatics SupportBarcelona, 11-12 July, 2005

studies on the pharmacology of mdma in humans repeated doses clinical studies
STUDIES ON THE PHARMACOLOGY OF MDMA IN HUMANSRepeated Doses Clinical Studies
  • Most MDMA users have more than one dose per rave/session
    • On the view of the non-linear kinetics of MDMA in humans, are those MDMA users ingesting repeated doses more prone to acute effects than those taking single doses?
    • Are MDMA users ingesting repeated doses just adjusting pharmacological effects over the time with relatively little risk for acute toxicological effects?

International Workshop on Pharmacogenomics and Pharmacogenetics: Current Challenges and Bioinformatics SupportBarcelona, 11-12 July, 2005

slide31

MDMA metabolic disposition after repeated doses

300

250

200

(second consecutive

dose)

150

plasma concentration (µg/L)

100

50

0

0

4

8

12

16

20

24

MDMA (100 mg), two doses

taken 24h apart

-After the 2nd dose MDMA metabolism

is reduced

-MDMA accumulates (about 30%,

accounting for the overall contribution

of CYP2D6 to MDMA disposition)

time (h)

300

(first dose)

250

200

150

plasma concentration (µg/L)

100

50

0

0

4

8

12

16

20

24

International Workshop on Pharmacogenomics and Pharmacogenetics: Current Challenges and Bioinformatics SupportBarcelona, 11-12 July, 2005

time (h)

MDMA

HMMA

HHMA

modeling of cyp2d6 inhibition by mdma
Modeling of CYP2D6 inhibition by MDMA
  • A typical recreational MDMA dose
  • could inactivate most hepatic CYP2D6
  • within an hour
  • The return to a basal level of CYP2D6
  • could take at least 10 days

Implications of Mechanism-Based Inhibition of CYP2D6 for the

Pharmacokinetics and Toxicity of MDMA. J Yang, M Jamei,

A Heydari, K R. Yeo, R de la Torre, M Farré, GT. Tucker, A

Rostami-Hodjegan. JPET (2005) in press

International Workshop on Pharmacogenomics and Pharmacogenetics: Current Challenges and Bioinformatics SupportBarcelona, 11-12 July, 2005

slide33

PM (*4/*4)

IM (*1/*4)

EM (*1/*1)

Plasma concentrations over time curves of MDMA,

HHMA and HMMA as a function of CYP2D6 genotype

MDMA

CYP2D6

HHMA

COMT

HMMA

International Workshop on Pharmacogenomics and Pharmacogenetics: Current Challenges and Bioinformatics SupportBarcelona, 11-12 July, 2005

slide34

Urinary recovery (0-24h) of MDMA and main metabolites as a function of CYP2D6 genotype

EM

IM

PM

International Workshop on Pharmacogenomics and Pharmacogenetics: Current Challenges and Bioinformatics SupportBarcelona, 11-12 July, 2005

slide35

Phenotypically EM subjects are “converted” to PM subjects after repeated doses

300

250

200

EM subjects

(second consecutive

dose)

150

plasma concentration (µg/L)

100

PM subjects

(any dose)

50

300

0

250

0

4

8

12

16

20

24

time (h)

200

300

concentration (µg/L)

150

EM subjects

(first dose)

250

100

200

50

150

plasma concentration (µg/L)

0

100

0

5

10

15

20

25

50

time (h)

0

0

4

8

12

16

20

24

International Workshop on Pharmacogenomics and Pharmacogenetics: Current Challenges and Bioinformatics SupportBarcelona, 11-12 July, 2005

time (h)

MDMA

HMMA

HHMA

mdma pharmacogenetics and acute toxicity iii
MDMA pharmacogenetics and acute toxicity (iii)
  • This risk has never been confirmed in humans after CYP2D6 genotyping of MDMA casualties. No bias towards PM subjects has been observed

Why?

  • Because repeated consumption of MDMA leads to a phenomenon of quasi phenocopying of subjects towards to the PM phenotype independently of the original genotype of subjects
  • Nevertheless subjects after MDMA ingestion have its CYP2D6 enzyme inhibited until newly enzyme is synthesised and this may lead to acute toxicity episodes as well as pharmacological interactions with drugs co-substrates of this enzyme

International Workshop on Pharmacogenomics and Pharmacogenetics: Current Challenges and Bioinformatics SupportBarcelona, 11-12 July, 2005

mdma pharmacogenetics and neurotoxicity i
MDMA pharmacogenetics and neurotoxicity (i)
  • Do genetic polymorphism in enzymes involved MDMA metabolic disposition contribute to any extend to neurotoxicity?
  • MDMA in animal models when injected directly into the brain produces 5-HT release but not neurotoxicity.
  • This observation suggests that MDMA must be metabolized peripherally in order to produce compounds that induce free radical formation and neurotoxicity in the brain

International Workshop on Pharmacogenomics and Pharmacogenetics: Current Challenges and Bioinformatics SupportBarcelona, 11-12 July, 2005

mdma pharmacogenetics and neurotoxicity ii
MDMA pharmacogenetics and neurotoxicity (ii)
  • Do genetic polymorphism in enzymes involved MDMA metabolic disposition contribute to any extend to neurotoxicity?
  • MDMA in animal models gives rise to HHMA in a reaction catalyzed partially by CYP2D1
  • HHMA is further metabolized to a compound capable of forming adducts with GSH, electrochemically active via a SOD-sensitive pathway
  • Therefore there may be a role for CYP2D6 in neurotoxicity as it participates in the bioactivation of MDMA

International Workshop on Pharmacogenomics and Pharmacogenetics: Current Challenges and Bioinformatics SupportBarcelona, 11-12 July, 2005

slide39

MDMA

HHMA

quinone

HHMA-GSH

adduct

MDMA METABOLISM

FORMATION OF GLUTATHIONE ADDUCTS

CYP2D6

SOD-sensitive pathway

TJ Monks ,SS Lau, RT Miller ,F Bai,DC Jones

Center for Molecular and Cellular Toxicology,

Division of Pharmacology and Toxicology,

College of Pharmacy, University of Texas at Austin

International Workshop on Pharmacogenomics and Pharmacogenetics: Current Challenges and Bioinformatics SupportBarcelona, 11-12 July, 2005

thioethers of mdma as putative toxic species involved in neurotoxicity
THIOETHERS OF MDMA AS PUTATIVE TOXIC SPECIES INVOLVED IN NEUROTOXICITY
  • Able to reproduce acute and long-term effects
  • Display in the brain a good selectivity for serotonergic axonic terminals
  • Biosynthesized at the hepatic level
  • Distributed to the rest of the body by blood circulation
  • Most likely benefit from glutathione specific transport mechanisms to cross the blood brain barrier

International Workshop on Pharmacogenomics and Pharmacogenetics: Current Challenges and Bioinformatics SupportBarcelona, 11-12 July, 2005

slide41

THIOETHERS OF MDMA ARE

FORMED IN VIVO IN RATS

As MDMA neurotoxicity depends on its

metabolic bioactivation, pharmacogenetics

of CYP2D6 becomes relevant again

International Workshop on Pharmacogenomics and Pharmacogenetics: Current Challenges and Bioinformatics SupportBarcelona, 11-12 July, 2005

Jones DC JPET 2005; 313: 422-31.

slide42

N-Ac-5-[cysteinyl]-HHMA

ANALYSIS OF THIOETHERS

ADDUCTS OF MDMA

5-[GSH]-HHMA

g-glutamyl

acetyl

5-[cysteinyl-glycyl]-HHMA

glycyl

5-[cysteinyl]-HHMA

International Workshop on Pharmacogenomics and Pharmacogenetics: Current Challenges and Bioinformatics SupportBarcelona, 11-12 July, 2005

Perfetti X et al 2005

slide43

THIOETHERS OF MDMA ARE

FORMED IN VIVO IN HUMANS

LC/MS-MS Assay in human urine

As MDMA neurotoxicity depends on its

metabolic bioactivation pharmacogenetics

of CYP2D6 becomes relevant again

N-Ac-5-Cys-HHMA

N-Ac-5-Cys-O-Me-HHMA (ISTD)

Hypothesis:

Are those subjects with more than one

functional copy of CYP2D6 gene more

prone to develop neurotoxicity?

About 1% of the dose (MDMA 75 mg) is

recovered in urine as N-Ac-5-Cys-HHMA

International Workshop on Pharmacogenomics and Pharmacogenetics: Current Challenges and Bioinformatics SupportBarcelona, 11-12 July, 2005

Perfetti X et al 2005

mdma pharmacogenetics and neurotoxicity iii
MDMA pharmacogenetics and neurotoxicity (iii)
  • Do genetic polymorphism in enzymes involved MDMA metabolic disposition contribute to any extend to neurotoxicity?
  • MDMA in animal models gives rise to HHMA in a reaction catalyzed partially by CYP2D6
  • HHMA is further metabolized to a compound capable of forming adducts with GSH, electrochemically active via a SOD-sensitive pathway
  • COMT contribution to metabolize HHMA to HMMA may counteract partially bioactivation of HHMA
  • COMT is a polymorphic enzyme in humans, therefore some genotypes may play a protective role in MDMA neurotoxicity

International Workshop on Pharmacogenomics and Pharmacogenetics: Current Challenges and Bioinformatics SupportBarcelona, 11-12 July, 2005

slide45

PM (*4/*4)

IM (*1/*4)

EM (*1/*1)

Plasma concentrations over time curves of MDMA,

HHMA and HMMA as a function of CYP2D6 genotype

MDMA

CYP2D6

HHMA

COMT

HMMA

International Workshop on Pharmacogenomics and Pharmacogenetics: Current Challenges and Bioinformatics SupportBarcelona, 11-12 July, 2005

slide46

Comparison of personality characteristics (TCI)

ecstasy vs. cannabis vs. control groups

ENTE Project

p<0.001

p<0.001

NS=novelty seeking

ST=self-transcendence

International Workshop on Pharmacogenomics and Pharmacogenetics: Current Challenges and Bioinformatics SupportBarcelona, 11-12 July, 2005

comt genotype and drug abuse ente project

Control group

(n=34)

35,3

20,6

44,1

Drug Users

(n=63)

COMT phenotypes (activities)

vs. genotype - Low – 158 Met/Met

- High – 158 Val/Val

- Medium –158Val/Met

12,9

37,1

50

COMT Genotype and Drug AbuseENTE Project

COMT genotypes associated

to high/medium enzyme activities

more prevalent among drug users

may protect individuals against

neurotoxicity

p<0.03, higher prevalence of

the 158 Val/Val genotype

International Workshop on Pharmacogenomics and Pharmacogenetics: Current Challenges and Bioinformatics SupportBarcelona, 11-12 July, 2005

summary
Summary
  • Two genetic polymorphic enzymes contributes to the variability of MDMA disposition in humans: CYP2D6 and COMT
  • CYP2D6 genotype is less relevant than expected in acute toxicity episodes because the inhibition of this enzyme by MDMA through the formation of an enzyme-metabolite complex
  • CYP2D6 and COMT participate in the formation and metabolism of HHMA, a MDMA metabolite involved in the formation of thioether adducts, putative neurotoxic species of MDMA
  • The balance between the activities of both enzymes may determine the susceptibility of MDMA users to develop neurotoxicity with different degrees of severity

International Workshop on Pharmacogenomics and Pharmacogenetics: Current Challenges and Bioinformatics SupportBarcelona, 11-12 July, 2005

pharmacogenetic and pharmacogenomic aspects of drug abuse does it makes sense
Pharmacogenetic and Pharmacogenomic Aspects of Drug Abuse Does it makes sense?

…diseases appearing to be "highly amenable to environmental

modification“ should take low priority in genomic research. …

K. R. Merikangas and N. Risch Science, 2003; 302:599-601

International Workshop on Pharmacogenomics and Pharmacogenetics: Current Challenges and Bioinformatics SupportBarcelona, 11-12 July, 2005

pharmacogenetic and pharmacogenomic aspects of drug abuse does it makes sense1
Pharmacogenetic and Pharmacogenomic Aspects of Drug Abuse Does it makes sense?

…addiction is not easily malleable; approximately 90% of smokers

who try to quit relapse within a year, with the majority relapsing

within a week…

Employing the power of genetic studies in understanding the

underlying biological, behavioral, and environmental factors will

enhance research on etiology, treatment, and prevention for

these complex diseases.

The diseases given low priority by Merikangas and Risch affect

about 30% of the U.S. population; those affected cannot afford

to wait when advances in genetics will have a significant public

health impact.

W Berrettini et al Science 2004;304:1445-1447

International Workshop on Pharmacogenomics and Pharmacogenetics: Current Challenges and Bioinformatics SupportBarcelona, 11-12 July, 2005

orpm1 gene and the a118g variant iv nicotine replacement therapy nrt abstinence
ORPM1 gene and the A118G variant (IV) Nicotine Replacement Therapy (NRT)Abstinence

International Workshop on Pharmacogenomics and Pharmacogenetics: Current Challenges and Bioinformatics SupportBarcelona, 11-12 July, 2005

orpm1 gene and the a118g variant iv nicotine replacement therapy nrt weight gain
ORPM1 gene and the A118G variant (IV) Nicotine Replacement Therapy (NRT)Weight gain

International Workshop on Pharmacogenomics and Pharmacogenetics: Current Challenges and Bioinformatics SupportBarcelona, 11-12 July, 2005

orpm1 gene and the a118g variant iv nicotine replacement therapy nrt mood disturbance
ORPM1 gene and the A118G variant (IV) Nicotine Replacement Therapy (NRT)Mood disturbance

International Workshop on Pharmacogenomics and Pharmacogenetics: Current Challenges and Bioinformatics SupportBarcelona, 11-12 July, 2005

slide54

Codeine Intoxication Associated with Ultrarapid CYP2D6 Metabolism

Yvan Gasche, M.D., Youssef Daali, Pharm.D., Ph.D., Marc Fathi, Ph.D., Alberto Chiappe, Silvia Cottini, M.D., Pierre Dayer, M.D., and Jules Desmeules, M.D.

Patient treated with codeine with three or more copies of CYP2D6

functional alleles that experienced a life-threatening opioid intoxication

(in combination with other factors)

NEJM 2004; 351:2827-2831

International Workshop on Pharmacogenomics and Pharmacogenetics: Current Challenges and Bioinformatics SupportBarcelona, 11-12 July, 2005