1. Clinical implications of pharmacogenetic research S:t Petersburg April 4, 2008 Professor Leif Bertilsson Dept. of Clinical Pharmacology Karolinska University Hospital, Huddinge Sweden

2. Leif Bertilsson2 Pharmacogenetics Pharmacogenomics

3. Leif Bertilsson3 Drug transporters Drug metabolising enzymes Drug receptors Drug receptor effectors Drug response Polymorphic impact on drug response Drug Metabolites + +++ + +

4. Leif Bertilsson4

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9. 9 Johansson et al., PNAS 90:1945-51, 1993, Aklillu et al., JPET 278: 441-6, 1996

10. Leif Bertilsson10 Dalén et al, 1998

11. Leif Bertilsson11 Frequency of subjects having duplicated/ multiduplicated CYP2D6 genes Sweden1-2 %Dahl et al, 1995 Denmark0.8 %Bathum et al, 1998 Germany3.6 %Sachse et al, 1997 Spain (Badajoz)7.0 %Agundez et al, 1995 Spain (Zaragoza)10 %Bernal et al, 1998 Saudi Arabia20 %McLellan et al, 1997 Ethiopia29 %Aklillu et al, 1996 Los Angeles, USA Caucasians4.3 %London et al, 1997 African-Americans4.9 %London et al, 1997

12. Leif Bertilsson12 Kawanishi et al 2004

13. Leif Bertilsson13

14. Leif Bertilsson14 Similarity among the CYP3A proteins CYP3A5 CYP3A7 CYP3A43 CYP3A4 84.1 88.1 75.8 CYP3A5 *** 81.9 75.8 CYP3A7 *** 71.5 CYP3A43 *** Gellner et al 2001

15. Leif Bertilsson15 Plasma concentrations of cholesterol and 4  -hydroxycholesterol in patients treated with different antiepileptics Antiepileptic drugCholesterol 4  Hydroxycholesterol nmol/lng/ml Valproate (n = 15) 4.5  0.828  15 Carbamazepine (n = 15) 5.8  1.5240  142 Phenytoin (n = 10) 5.1  1.0214  154 Phenobarbital (n = 5) 4.9  1.1239  226

16. Leif Bertilsson16 4β-Hydroxycholesterol in three populations p<0.000001p<0.01 p<0.000001

17. Leif Bertilsson17 Haplotype frequencies *3 6986A>G *6 14690>A *7 27131- 27132insT SwedesKoreansTanzanians CYP3A5*1AGT0.070.170.53 CYP3A5*3G*GT0.930.800.17 CYP3A5*6AA*T--0.18 CYP3A5*7AGTT*--0.12 CYP3A5*3 + *7G*GTT*-0.03

18. Leif Bertilsson18 Impact of CYP3A5 on 4β-hydroxycholesterol Number of CYP3A5*1 alleles

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20. Leif Bertilsson20 Inhibition of metoprolol metabolism and potentiation of its effects by paroxetine in routinely treated patients with acute myocardial infarction (AMI) Ksenia Goryachkina, Aleksandra Bubello, Svetlana Boldueva, Svetlana Babak, Ulf Bergman, Leif Bertilsson Eur. J. Clin. Pharmacol. 2008;64:275-282

21. Leif Bertilsson21 Methods: 187 patients (61% men, age 60±11 years (36-85) with confirmed AMI CYP2D6 *3,*4, and gene duplication Metoprolol and α-hydroxy metoprolol concentrations were measured in plasma 0,2,6 and 12 hours after metoprolol intake Heart rate and blood pressure was measured at the times of sampling Clinical variables were taken from case histories (baseline and discharge heart rate, metoprolol dose at discharge, concomitant diseases, severity of AMI, heart failure etc) number of functional CYP2D6 alleles Heart rates on the adjusted metoprolol dose were higher with more functional alleles (p<0.05) Pharmacodynamics:Pharmacokinetics: Metoprolol plasma concentration AUC Is determined by CYP2D6 genotype P<0.001

22. Leif Bertilsson22 Goryachkina et al, 2008

23. Leif Bertilsson23 Active CYP2D6 genes in AMI patients without ventricular rhythm disturbances (VRD) (n=177) and with VDR (N=23) in hospitalized Russian patients Goryachkina et al, 2008 CYP2D6 duplication 4/173 (2 %) 5/18 (22 %) p = 0.0002

24. Leif Bertilsson24 Bertilsson et al: Debrisoquine hydroxylation and personality, Lancet 1989 Poor hydroxylators had significantly lower scores in the Karolinska psychasthenia scale (p<0.05) and had a higher frequency of extreme responses (p<0.01) than extensive hydroxylators. Low psychasthenia scores imply high vitality, alertness, efficiency, and ease of decision-making. The poor hydroxylators’ lack of hesitation was also reflected in the more frequent choice of extremes. These personality characteristics agreed well with the impression we had before our study.