抗癫痫药遗传药理学研究进展

抗癫痫药遗传药理学研究进展

抗癫痫药遗传药理学研究进展

抗癫痫药遗传药理学研究进展

Differential drug efficacySame symptoms Same findings Same disease (?) Same Drug…. Genetic Differences Different Effects

Possible Reasons: Non-Compliance… Drug-drug interactions… Chance… Or….

?

抗癫痫药遗传药理学研究进展

Polymorphisms Affect Drug Handling and Drug Targets

Genetic Polymorphism

Pharmacokinetics Metabolism Transporters

Pharmacodynamics Receptors Ion Channels

Protein Binding

Enzymes

抗癫痫药遗传药理学研究进展

Normal Population Distribution

Percent of subjects per 0.5 Units/ml of activity

10

5

0 0 10 15 20Enzyme activities, Units/ml

抗癫痫药遗传药理学研究进展

Genetic polymorphism of drug metabolizing enzymes

Percent of subjects per 0.5 Units/ml of activity

10

5

Slight adverse effects

Severe adverse effects

0 0

5

10

15

20

Enzyme activities, Units/ml

抗癫痫药遗传药理学研究进展

Canditated Genes associated with pharmacogenetics of antiepileptic drugs

ProductMDR1/ABCB1 SCN1A GABBR1 GABA-B TNFα HLA CYP3A CYP2C19 CYP2C9 CYP2A6 MRP OCTN2 UGT 1A6 CYP1A2 CYP2D6 CYP2C8 PXRPRNP

FunctionTransmembrane transport Movement of sodium ions cross membrane Membrane receptorAssociated with the inflammatory pathway Associated with immune response. Associated with hydroxylation Associated with hydroxylation Omega oxidation pathway Associated with oxidation Transmembrane transport Transmembrane transport Associated with glucuronidation pathway Associated with hydroxylation Associated with hydroxylation Associated with hydroxylation Associated with indirect metabolism in hydroxylation pathway Associated with neuron protection

P-glycoprotein α1 subunit sodium channel Gamma-aminobutyric acid receptor BSubunit of tumour necrosis factor HLA Cytochrome p450 enzyme Cytochrome p450 enzyme Cytochrome p450 enzyme Cytochrome p450 enzyme Multidrug resistance-associated protein Organic cation transport protein Uridine diphosphate glycosyltransferase Cytochrome p450 enzyme Cytochrome p450 enzyme Cytochrome p450 enzyme Pregnane X receptor Cellular prion protein

抗癫痫药遗传药理学研究进展

Drug transporters

抗癫痫药遗传药理学研究进展

Drug-resistance Epilepsy

pharmacogenetics40%--50%

抗癫痫药遗传药理学研究进展

Model of the proposed role of cell specific MDR1 expression in epileptic brain

抗癫痫药遗传药理学研究进展

MDR1 expression and drug-resistance epilepsy

Immunohistochemical detection of MDR1 expression in human drugrefractory epileptic brain.BMC Med. 2004; 2: 37

抗癫痫药遗传药理学研究进展

MDR1 polymorphism and drug-resistance epilepsy

C3435TSchematic representation of the multidrug resistance-1 (MDR1) gene and putative protein secondary structure.

抗癫痫药遗传药理学研究进展

MDR1 polymorphism and drug-resistance epilepsySummary of Genotype and Phenotype Data Total No.

Phenotype

MDR1 3435 Genotype CC CT TT

Drug-resistant epilepsy Drug-responsive epilepsy Control

200 115 200

no. (%) 55 (27.5) 106 (53.0) 39 (19.5) 18 (15.7) 63 (54.8) 34 (29.6) 37 (18.5) 116 (58.0) 47 (23.5

For all 315 patients with epilepsy, patients with drug-resistant epilepsy were more likely than those with drug-responsive epilepsy to have the CC genotype than the TT genotype (x2=7.65, P=0.006).

N Engl J Med 2003;348:1442-8.

抗癫痫药遗传药理学研究进展

Up

take of carnitine and organic cations by HEK293 cells expressing wild-type and S467C-mutant OCTN2

Compounds L-[3H]Carnitine [3H]Acetyl-carnitine

Time min 3 5

Wild-Type 884.2 ± 13.94 (100) 597.8 ± 7.60 (100)

S467C Mutant µl/mg protein 102.8 ± 1.20 (9.9)* 103.9 ± 5.38 (13.5)*

[14C]TEA30[3H]Pyrilamine [3H]Quinidine [3H]Verapami

305 5 l5

46.5 ± 0.99 (100)993.5 ± 9.95 (100) 1524.5 ± 23.30 (100) 2539.9 ± 36.43 (100)

48.1 ± 1.30 (104.8)873.9 ± 4.42 (75.0)* 1446.5 ± 21.20 (84.3) 2540.1 ± 36.81 (103.0)

* Significantly different from the uptake by wild-type OCTN2 by Student's t test (p < 0.05).

Pharmacology 2002, 302: 1286-1294

抗癫痫药遗传药理学研究进展

Use of Verapamil as a Petential P-Glycoprotein Inhibitor in a Patient With Refractor EpilepsyDays Since Prior Hospitalization150 120 90 60 30 0 Aug 01 Oct 01 Dec 01 Feb 02 Apr 02 Jun 02 Aug 02 Oct 02 Nov 02 Jan 03 Apr 03

Date of Hospitalization

Verapamil Started Jan 03

The Annals of Pharmacotherapy 2004,38:1631-4

抗癫痫药遗传药理学研究进展

Drug metabolism

抗癫痫药遗传药理学研究进展

Enzymes associated with major metabolic pathways *Enzymes associated with major metabolic pathways

CarbamazepineValproic acid Phenytoin

CYP3A4, CYP1A2, CYP2A6, CYP2C8, CYP2C19, CYP2D6,UGT1A6, UBG2B 50% by UGT, CYP2C9, CYP2C19 CYP2C9, CYP2C19, UGT

PhenobarbitalPrimidone Gabapentin Tiagabine Topiramate Felbamate Lamotrigine

CYP2C9, CYP2C19CYP2C9, CYP2C19, 95% excreted unchanged by kidney, rest by transaminase and vitamin B6 CYP3A4, UGT 80% excreted unchanged by kidney, rest CYP2C9, CYP2C19 CYP2E1, CYP3A4, CYP2C19 More than 70% UGT1A4, 10% excreted unchanged

*Alteration in any enzyme important in metabolism can alter the metabolite population formed affecting efficacy and adverse event profile