解析 CYP2D6 的遗传药理学
EM Extensive Metabolizer
Griese et al. Pharmacogenetics 1998, Raimundo et al. CPT 2004, Toscano et al. Pharmacogenetics 2006
Individuals
40 30 20 10
UM ultrarapid metabolizer ~ 10-15 %
IM Intermediate Metabolizer ~ 10-15 %
PM Poor Metabolizer ~ 5-10 % Caucasians
0.1
100 MRS 1 10 华中科技大学同济医学院附属同济医院药学部
FDA drug label change and public health advisories
Health Canada Public Advisory
May 10, 2006
Aug. 21, 2008
Aug 17, 2007
华中科技大学同济医学院附属同济医院药学部
August 20, 2009

Rare or lack phenotypic effect

Caucasian
*1G and *22 allele
华中科技大学同济医学院附属同济医院药学部
CYP3A4 SNPs
CYP3A4*1G reduced activity higher plasma levels
Less
fentanyl required side effects
OPRM1 and Fentanyl
118A>G
Higher
fentanyl requirement (Zhang 2011) VAS pain score (Wu 2009)
Higher
118A>G relevant?
Liao 2013: N=97, post-operative pain, fentanyl requirement+AEs CYP3A4*18 >> A118G

Pharmacodynamic: target and downstream signaling cascade
Mu-opioid receptor, inwardly rectifying potassium channel etc

Pain sensitivity: susceptibility to pain
Metabolism fentanyl
华中科技大学同济医学院附属同济医院药学部
Байду номын сангаас
CYP3A4 Gene

Important drug metabolizing enzyme Highly expressed in liver and intestine broad substrate specificity (app. 50%) Identified SNPs 22 alleles identified (CYPallele homepage)
More
Studies
Dong (2012),Yuan (2011) and Zhang (2010): Lower fentanyl requirement postoperative
CYP3A4*22
华中科技大学同济医学院附属同济医院药学部
PD RELATED GENES
华中科技大学同济医学院附属同济医院药学部
Kelly, Rieder, van den Anker et al. More codeine fatalities after tonsillectomy in North American children. Pediatrics 2012;129(5):1343-7 华中科技大学同济医学院附属同济医院药学部
CYP2D6基因多态性对术后吗啡消耗量的影响

人体内内源性类似于吗啡的化合物已经被 鉴定 CYP2D6是吗啡生物合成途径中的关键步骤 对141名术后患者进行吗啡耗费量检测， CYP2D6 的活性状况用Amplichip Microarray来检测

Candiotti KA, Yang Z, Rodriguez Y et al. Pain Med. 2009 Jul华中科技大学同济医学院附属同济医院药学部 Aug;10(5):799-805
30 20
10 0
0
5
10
15
20
25
time [h]
华中科技大学同济医学院附属同济医院药学部 Eckhardt et al., Pain 1998
Explanation:
medication mother due to episiotomy pain:
codeine 60 mg plus paracetamol 1000 mg every 12 hrs for
codeine
site of action
Cytochrome P450 2D6
60
morphine [pmol/ml]
50 40
morphine
plasma morphine levels after 170 mg codeine p.o.
Poor Metabolizer
Extensive Metabolizer
2. <10% translated to human pain
3. Opioid + genetic ≈ 2000 hits
华中科技大学同济医学院附属同济医院药学部
Division of genes

Pharmacokinetic: affect the availability at the site of action Phase I and II enzymes, transporters etc.
Estimated 1846 newborn infants are at risk for this codeine ADR annually in Canada
(340,000 births, 73% breastfed, 52% mothers receive codeine post-childbirth,1.4% risk genotype)
Drug
Drug
PM
“Functional” overdose
Stable metabolites, Excretion
华中科技大学同济医学院附属同济医院药学部
CYP2D6 Pharmacogenetics
CYP2D6 activity displays bimodal distribution in
华中科技大学同济医学院附属同济医院药学部
PAIN SENSITIVITY GENES
华中科技大学同济医学院附属同济医院药学部
Pain sensitivity genes
Action potential
SCN9A
Α-subunit Nav1.7 channel, nociceptive neurons R1150W increased sensitivity to pain (Reimann 2010)
autopsy: no abnormality blood concentration of morphine (metabolite of codeine): 70 ng/mL versus 0-2.2 ng/mL (typical)
华中科技大学同济医学院附属同济医院药学部
可待因的遗传药理学
华中科技大学同济医学院附属同济医院药学部
Transporters
Receptors
Phosphatases 2nd messengers
Targets
Protein kinases
GI Lumen
Blood
Cell
华中科技大学同济医学院附属同济医院药学部
Candidate genes
1. 410 pain genes
Sodium channel, interleukines etc.
华中科技大学同济医学院附属同济医院药学部
PK RELATED GENES
华中科技大学同济医学院附属同济医院药学部
一. 药物代谢酶
华中科技大学同济医学院附属同济医院药学部
CYP2D6 Pharmacogenetics
EM
Stable metabolites, Excretion
Caucasian subjects
5-10% of Caucasian population deficient in
CYP2D6 activity
“Poor metabolizers” or “PMs” have two
“inactive” forms (alleles) of the CYP2D6 gene
full-term healthy male infant day 7 pp: intermittent periods of difficulty in breastfeeding day 11: the baby had regained his birthweight day 12: grey skin, milk intake had fallen day 13: the baby was found dead
304A>G Lower fentanyl requirement (Landau 2009) Association with morphine requirement not found (Wong 2010)
华中科技大学同济医学院附属同济医院药学部