Ethnic Differences in Drug Metabolism ETHNICITY AND PSYCHOTROPIC RESPONSE Bridging Cultures: Improving Evaluation & Treatment of Cognitive 8 March 28 Keh-Ming Lin, M.D., M.P.H. Professor Emeritus of Psychiatry, UCLA President, Taiwanese Society of Biological Psychiatry and Neuropsychopharmacology (TSBPN) Director, Division of Mental Health and Substance Abuse Research National Health Research Institutes (NHRI) Dosage and side effects Pharmacokinetics Pharmacodynamics Pharmacogenetics PREVALENCE OF FLUSHING RESPONSE BY ETHNCIITY METABOLISM OF ALCOHOL Alcohol Fatty acid synthesis 8% 7% 6% 5% 4% 3% 2% 1% % Asians Amerindians Caucasians African Americans Alcohol dehydrogenase (ADH) Acetaldehyde + Acetaldehyde NADH dehydrogenase (ALDH) Acetate NADH AcetylCoA + NADH NADH Pyruvate lactate Citric acid cycle 1
NEUROLEPTIC DOSAGE FOR HOSPITALIZED PATIENTS:ASIANS VS CAUCASIANS ETHNICITY AND PHARMACOKINETICS Single Dose Nortriptyline Kinetics 25 2 15 1 5 Maximal Dosage Asians Stabilized Dosage Caucasians Lin & Finder, Am J Psychiatry 14:49-491, 1983 AUC (ng/ml/hr) 5 1 15 Japanese (5 mg) Caucasians (1 mg) Maximal Haloperidol Concentration After.5 mg i.m. Haloperidol Therapeutic Lithium Concentrations 5 4 3 2 1 Serum Haloperidol (ng) Lithium Levels (meq/l) 1.2 1.8.6.4.2 Asian Caucasian Caucasians Japanese Taiwanese Shanghai Hong Kong 2
Propranolol Response: Chinese vs Caucasians Factors Determining Pharmacological Response 8 propranolol concentrations 7 6 5 4 3 2 Chinese Caucasians Pharmacokinetics Genetics CYP3A Environmental factors Pharmacodynamics 1 heart rate (IC2) blood pressure (IC1) CYP2D6 Dosage Side effects Clinical response 5-HTT Zhou et al., NEJM 32:565-7, 1989 DRUGS METABOLIZED BY CYP2D6 ANTIDEPRESSANTS amitriptyline, clomipramine, imipramine, desipramine nortriptyline, trimipramine,, N-desmethylN desmethyl-clomipramine fluoxetine, norfluoxetine, paroxetine, venlafaxine (sertraline) NEUROLEPTICS chlorpromazine, thioridazine, perphenazine, haloperidol reduced haloperidol resperidone, clozapine, sertindole OTHERS codeine,, opiate, propranolol, dextromethorphan,, etc. 3
DRUGS METABOLIZED BY CYP3A4 Typical Antipsychotics- thioridazine*, haloperidol* Atypical Antipsychotics-clozapine clozapine*, quetiapine, risperidone*, sertindole*, ziprasidone Antidepressants-nefazadone nefazadone, sertraline, mirtazepine*, tricyclic antidepressants Mood Stabilizers-carbamazepine carbamazepine, gabapentin, lamotrigine Benzodiazepines- alprazolam, clonazepam, diazepam*, midazolam, triazolam, zolpidem Calcium Channel Blockers- diltiazem, nifedipine, nimodipine, verapamil, androgens, estrogens, erthyromycin, terfenadine, cyclosporine, dapsone, ketaconazole, lovastatin, lidocaine alfentanil, amiodarone, astemiazole,, codeine*, Viagra Nifedipine-Herb Interactions: Nifedipine Plasma Levels (ng( ng/ml) Mean NF (ng/ml) 6 5 4 3 2 1 NF Only NF + SJW NF + PG NF + GB 1 2 3 4 5 6 Time (Hr) NIFEDIPINE METABOLISM IN ASIAN INDIANS AND BRITISH WHITES 4
Pharmacokinetics of Acetylcholinesterase Inhibitors Some Therapeutic Targets of Antidepressants SSRI (Paroxetine Citalopram, etc) dose t 1/2 tmax metabolism Cognex Tacrine 12-16mg 2-3h 1-2h CYP1A2 Aricept Donepezil 5-1mg 7h 3-4h CYP3A CYP2D6 Reminyl Galantamine8-16mg 7h 1h CYP3A CYP2D6 Exelon rivastigmine9.5mg patch/11.5h sulfate conjugation Serotonin Transporter Serotonin system Norepinephrine Dopamine, and other neurotransmitter systems Serotonin Transporter Gene (SLC6A4) Polymorphism l % 1% 2% 3% 4% 5% 6% 7% 8% African American European American Ashkenazi Sephardic Japanese Murphy et al., Biol Psychiatry, 23;54:665 673 5
Apolipoproteinε4 Genetic Polymorphism % 5% 1% 15% 2% 25% 3% 35% 4% Melanesians Laplanders African Blacks African Americans Caucasians Asian Indians Malays Mexicans East Asians Implications for Geriatric Populations in Multiethnic and Multicultural Settings Mechanisms responsible for age effects on drug responsible similar to those for cross-ethnic effects Interactions among these variables (age, gender, ethnicity, dietary practices, etc) mostly unknown and require further research Factors Determining Pharmacological Response PSYCHOPHARMACOLOGY IN THE SOCIOCULTURAL CONTEXT Pharmacokinetics Dosage Side effects Genetics Pharmacodynamics Clinical response Environmental factors Clinician-Patient Interactions Institutional and Clinicians Ideologies and Biases Patients and Their Families Beliefs and Expectations Adherence (Compliance) The Effect of Expectation Placebo Response Interpretation of Side-Effects Goals of Treatment Use of Alternative Methods Herbs Healing Methods Based on Alternative Medical Systems Indigenous Healing 6
Side Effects of Lithium in Hong Kong Bipolar Patients Patients Controls Lee 1994 1.2 1.8.6.4.2 Polydypsia weight gain Tiredness slowed thinking Loss of Creativity Metalic Taste FACTORS AFFECTING DRUG RESPONSE Culture Placebo Effects Adherence (Compliance) Gender Age Diet Herbs Social Support Smoking Alcohol Caffeine GENETICS Exercise Personality Drugs Disease THEORETICAL ISSUES Biological diversity vs cultural diversity Danger of color-blindness vs danger of Stereotyping Cross-ethnic variability almost always superimposes on even larger intra- group variability Cross-cultural/cross cultural/cross-ethnic validation and universality 7
PSYCHOPHARMACOLOGY IN THE SOCIOCULTURAL CONTEXT Clinician Professional Ideology Institutional Policies Financial Constraints Influence from the Industry Patient Cultural Beliefs Family and Friends Past Experiences Psychopathology 8