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Igangværende forskning…INDICES
INDIvidualised drug therapy based onpharmacogenomics: focus on
carboxylesterase 1 (CES1)
Kim Dalhoff
Kim Dalhoff● Professor of Clinical Pharmacology
(toxicology), MD, DMSc, FEAPCCT● Specialist in Clinical Pharmacology and
Hepatology● Consultant at the Department of Clinical
Pharmacology, Bispebjerg andFrederiksberg Hospital & Giftlinjen(DPIC)
● E-mail: [email protected]
Outline
● Introduction to CES1●Variation in drug response● INDICES background (key
studies)● INDICES – WP2
Carboxylesterase 1 (CES1)● Phase I enzyme involved in
hydrolysis of ester andamido-type drugs, includingactivation of prodrugs
● Encoded by a genecomposed of 14 exonsspanning 30 kb onchromosome 16
Sustrate spectrum of CES1 –metabolism and bioactivation
● Methylphenidate● Cocaine and heroin● Imidapril and derapril (angiotensin-converting
enzyme inhibitors)● Oxybutynin (anticholinergic)● Oseltamivir (avian flu)● Irinotecan● Environmental compunds such as phthalates,
pyrethroid and organophosphates
CES is involved in the hydrolysis ofseveral xenobiotics and endogenousesters and amides●CES1 (liver)●CES2 (intestines)● CES3● CES4
METHYLPHENIDATELack of response● Up to 30% of patients receiving MPH are non-respondersAdverse effectsVery common (> 10%)● Decreased appetite, stomach pain, headache and insomniaCommon (1-10%)● Weight loss● Nausea● Diarrhoea and vomiting● Cardiac effects (tachycardia, elevated systolic blood pressure and arrhythmia)Not common (0.1-1%)● Confusion● Psychosis● Breast pain and dyspnoea● Abnormal dreams● Allergic reactions
Large variation in drug responsebetween individuals
● Some patients get the desired
effects (responders)● A lot of patients only get little
effect (partially responders) orno effect at all (non-responders)
● The remaining group ofpatients get adverse drugreactions
Solution to the problems is(may be) individualization ofdrug dose and type of drug
● ”One size fits all” – ”standardtreatment”● A patient is classified into a subgroup
with a differential therapeutic response● Personalized medicine, fitted to the
single individual
Various types of genetic variation
● Single nucleotide variation● Indels (< 1kb)● Copy number variation (> 1 kb)
Structural variation
Normal
Deletion
Duplication
Triplication
Inversion
Deletions and duplications = copy nummer variationsSize is always > 1 kb
A focused study of the subject’sCES1 gene
DNA sequencing detects two coding region SNP’s inexons 4 and 6● Exon 4 (codon 143) non-conservative substitution
p.Gly143Glu● Exon 6 (codon 260) deletion leading to a frameshift
mutation p.Asp260fsp.Gly143Glu allele frequency 3.7% (white population)(Asian 0%)p.Asp260fs extremely rare (none in 925 DNA samples)
H-J Zhu et al. Am J Hum Gen 2008; 82: 1241
●WP1: Drug and metabolite study●WP2: Pharmacokinetic study●WP3: Genetic study●WP4: Pharmacometabolomics●WP5: Systems pharmacology and
metabolomics●WP6: Clinical study A – ADHD●WP7: Clinical study B – CHF
WP2: Individual differences in themetabolism of drugs
● Genetic screening of 150 healthy volunteers forCES1 variants (enrichment of the study populationto increase the number of rare variants)
● Selection of 40-50 individuals based on CES1genotypes
● Pharmacokinetic study with methylphenidate andenalapril
Claus Stage, phd-student
Selection of subjects● Group 1 (n=16) Two copies of CES1A1 (control
subjects)● Group 2 (n=5) Four copies of CES1 (2 CES1A1 and 2
CES1A2● Group 3 (n=6) Subjects with pGly143Glu SNP● Group 4 (n=2) Three copies of CES1 and CES1A2
(the variant with increased promoter activity)● Group 5 (n=4) Subjects with the CES1A1c variant● Group 6 (n=10) Tree copies of CES1 and CES1A2
(variants with normal promoter)To be continued…