抗癫痫药遗传药理学研究进展ppt课件

1、抗抗癫痫药遗传药癫痫药遗传药理理学研讨进学研讨进展展Differential drug efficacySame symptomsSame findingsSame disease (?)Same Drug.Different Effects?Genetic DifferencesPossible Reasons: Non-Compliance Drug-drug interactions ChanceOr.Polymorphisms Affect Drug Handling and Drug Targetsl Receptorsl Ion Channelsl Enzymesl Metabol

2、isml Transportersl Protein BindingNormal Population Distribution10500101520Enzyme activities, Units/mlPercent of subjects per0.5 Units/ml of activityGenetic polymorphism of drug metabolizing enzymes105005101520Enzyme activities, Units/mlPercent of subjects per0.5 Units/ml of activitySlight adverse e

3、ffectsSevere adverse effects Product FunctionMDR1/ABCB1 P-glycoprotein Transmembrane transportSCN1A 1 subunit sodium channel Movement of sodium ions cross membraneGABBR1 Gamma-aminobutyric acid receptor B Membrane receptorGABA-BTNF Subunit of tumour necrosis factor Associated with the inflammatory p

4、athway HLA HLA Associated with immune response. CYP3A Cytochrome p450 enzyme Associated with hydroxylationCYP2C19 Cytochrome p450 enzyme Associated with hydroxylationCYP2C9 Cytochrome p450 enzyme Omega oxidation pathwayCYP2A6 Cytochrome p450 enzyme Associated with oxidationMRP Multidrug resistance-a

5、ssociated protein Transmembrane transportOCTN2 Organic cation transport protein Transmembrane transportUGT 1A6 Uridine diphosphate glycosyltransferase Associated with glucuronidation pathwayCYP1A2 Cytochrome p450 enzyme Associated with hydroxylationCYP2D6 Cytochrome p450 enzyme Associated with hydro

6、xylationCYP2C8 Cytochrome p450 enzyme Associated with hydroxylationPXR Pregnane X receptor Associated with indirect metabolism in hydroxylation pathwayPRNP Cellular prion protein Associated with neuron protectionCanditated Genes associated with pharmacogenetics of antiepileptic drugsDrug transporter

7、spharmacogenetics40%-50%Drug-resistance EpilepsyModel of the proposed role of cell specific MDR1 expression in epileptic brain Immunohistochemical detection of MDR1 expression in human drug-refractory epileptic brain. BMC Med. 2004; 2: 37 MDR1 expression and drug-resistance epilepsyC3435TSchematic r

8、epresentation of the multidrug resistance-1 (MDR1) gene and putative protein secondary structure. MDR1 polymorphism and drug-resistance epilepsyN Engl J Med 2003;348:1442-8. Summary of Genotype and Phenotype Data TotalPhenotype No. MDR1 3435 Genotype CC CT TT no. (%)Drug-resistant epilepsy 200 55 (2

9、7.5) 106 (53.0) 39 (19.5)Drug-responsive epilepsy 115 18 (15.7) 63 (54.8) 34 (29.6)Control 200 37 (18.5) 116 (58.0) 47 (23.5For 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

10、 (x2=7.65, P=0.006).MDR1 polymorphism and drug-resistance epilepsy Compounds Time Wild-Type S467C Mutant min l/mg proteinL-3HCarnitine 3 884.2 13.94 (100) 102.8 1.20 (9.9)*3HAcetyl-carnitine 5 597.8 7.60 (100) 103.9 5.38 (13.5)*14CTEA30 30 46.5 0.99 (100) 48.1 1.30 (104.8)3HPyrilamine 5 993.5 9.95 (

11、100) 873.9 4.42 (75.0)* 3HQuinidine 5 1524.5 23.30 (100) 1446.5 21.20 (84.3)3HVerapami l5 2539.9 36.43 (100) 2540.1 36.81 (103.0)* Significantly different from the uptake by wild-type OCTN2 by Students t test (p 0.05).Uptake of carnitine and organic cations by HEK293 cells expressing wild-type and S

12、467C-mutant OCTN2 Pharmacology 2002, 302: 1286-1294 VerapamilStarted Jan 03Date of HospitalizationDays Since Prior HospitalizationUse of Verapamil as a Petential P-Glycoprotein Inhibitor in a Patient With Refractor EpilepsyThe Annals of Pharmacotherapy 2004,38:1631-4Drug metabolism Enzymes associate

13、d with major metabolic pathwaysCarbamazepine CYP3A4, CYP1A2, CYP2A6, CYP2C8, CYP2C19, CYP2D6, UGT1A6, UBG2BValproic acid 50% by UGT, CYP2C9, CYP2C19Phenytoin CYP2C9, CYP2C19, UGTPhenobarbital CYP2C9, CYP2C19Primidone CYP2C9, CYP2C19,Gabapentin 95% excreted unchanged by kidney, rest by transaminase a

14、nd vitamin B6Tiagabine CYP3A4, UGTTopiramate 80% excreted unchanged by kidney, rest CYP2C9, CYP2C19Felbamate CYP2E1, CYP3A4, CYP2C19Lamotrigine More than 70% UGT1A4, 10% excreted unchanged*Alteration in any enzyme important in metabolism can alter the metabolite population formed affecting efficacy

15、and adverse event profileEnzymes associated with major metabolic pathways * Genotype n (%) Mean dose (mg dd) Mean oncentration (range) (mg/l) (range)Total 60 253 15.7CYP2C9*1/*1 37 (62%) 287 (75425) 15.8 (2.236.4)CYP2C9*1/*2 9 (15%) 201 (150225)* 16.1 (9.031.2)CYP2C9*1/*3 9 (15%) 196 (150275)* 13.8

16、(5.118.2)CYP2C9*2/*3 2 (3%) 175 (150200)* 20.4 (12.827.9)CYP2C9*2/*2 3 (5%) 217 (175275)* 14.0 (10.617.6)*P 0.01 versus CYP2C9*1/*1CYP2C9 genotype distribution and mean phenytoin maintenance Dose/mean phenytoin steady-state serum concentration per enotypePharmacogenetics 2001, 11:287-291 Genotype n (%) Mean dose (mg dd) (range)Total 36 260CYP2C9*1/*1 19 (53%) 314 (200425)CYP2C9*1/*2 6 (17%) 193 (150225)*CYP2C9*1/*3 7 (19%) 202 (150275)*CYP2C9*2/*3 1 (3%) 150*CYP2C9*2/*2 3 (8%) 217 (175275)*PA genotypePNAS 20