Pharmacogenetic Testing of Cytochrome P450 Drug Metabolizing Enzymes in a Case Series of Patients with Prader-Willi Syndrome
Abstract
:1. Introduction
1.1. Prader-Willi Syndrome (PWS)
1.2. Pharmacogenetics of the Cytochrome P450 System
2. Methods
3. Results
3.1. Cytochrome P450 Genotypes, Phenotypes and Genetic Subtype of PWS
3.2. CYP2D6
3.3. CYP2B6
3.4. CYP2C19
3.5. CYP2C9
3.6. CYP3A4
3.7. CYP1A2
4. Discussion
4.1. Drug–Drug Interactions
4.2. Specific Relevance of Cytochrome P450 Enzyme System to PWS
4.3. Non-Genetic Factors Affecting Drug Pharmacokinetics in PWS
4.4. Limitations and Future Directions
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Appendix A
Cytochrome P450 | Chromosome Location | Common Alleles and Phenotypic Action |
---|---|---|
CYP2D6 | 22q13.1 | *1 (wildtype); *2 (normal); *2A (increased action); *9, *10, *17, *41 (decreased action); *4, *3,* 5, *6 (inactive). |
CYP2B6 | 19q13.2 | *1 (wildtype); *2, *5, *17 (normal); *4, *22 (increased action); *6, *7, *9, *16, *19, *20 (decreased action); *8, *12, *13, *18,*24 (inactive). |
CYP2C19 | 10q24.1–q24.3 | *1 (wildtype); *11, *13, *15, *18,*28 (normal); *17 (increased action); *9, *10, *16, *19, *25, *26 (decreased action); *2-*8, *22, *24, *35-*37 (inactive). |
CYP2C9 | 10q23.33 | *1 (wildtype); *9 (normal); *2, *3 (decreased action); *6, *15, *25 (inactive). |
CYP3A4 | 7q22.1 | *1 (wildtype); *7, *9, *10 (normal); *1B, *2-*6, *8, *11-*13, *15-*18, *22 (decreased action); *20, *26 (inactive). |
CYP1A2 | 15q24.1 | *1, *1A, *1B (wildtype); *1D (T-delT), *1F(C/A) increased action when induced; *1C(G/A); *1K(C/A); *3(T/C), *4(A/T), *7(G/A) (decreased action). |
CYP2D6 | CYP2B6 | CYP2C19 | CYP2C9 | CYP3A4 | CYP1A2 | |||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
Lab | Alleles | PT | Alleles | PT | Alleles | PT | Alleles | PT | Alleles | PT | Alleles | PT |
GS | *1/*1 | EM | *1/*6 | IM | *1/*1 | EM | *1/*1 | EM | *1/*1 | EM | *1F/*1B | UM |
GS | *4/*41 | PM | *1/*6 | IM | *1/*17 | EM | *1/*1 | EM | *1/*1 | EM | *1A/*1B | EM |
GS | *2/*17 DUP | EM | *1/*6 | IM | *1/*17 | EM | *1/*1 | EM | *1/*1 | EM | *1A/*1B | EM |
GS | *2/*4 | IM | *1/*1 | EM | *1/*17 | EM | *1/*1 | EM | *1/*22 | IM | *1A/*1B | EM |
GS | *1/*10 | IM | *1/*6 | IM | *17/*17 | UM | *1/*1 | EM | *1/*1 | EM | *1F/*1B | UM |
GL | *2A/*5 | IM | *1/*5 | EM | *1/*1 | EM | NA | NA | *1/*22 | IM | *1A/*1A | EM |
GS | *4/*4 | PM | *1/*1 | EM | *1/*1 | EM | *1/*1 | EM | *1/*1 | EM | *1F/*1B | UM |
GS | *1/*41 | EM | *1/*1 | EM | *1/*2 | IM | *1/*1 | EM | *1/*1 | EM | *1F/*1B | UM |
GS | *1/*9 | IM | *1/*6 | IM | *1/*17 | EM | *1/*1 | EM | *1/*1 | EM | *1F/*1B | UM |
GS | *1/*9 | IM | *1/*1 | EM | *1/*17 | EM | *1/*2 | IM | *1/*1 | EM | *1A/*1B | EM |
GL | *1/*4 | IM | *1/*5 | EM | *1/*1 | EM | *1/*2 | IM | *1/*1 | EM | *1A/*1F | HI |
GL | *1/*4 | IM | *1/*6 | IM | *1/*1 | EM | *1/*1 | EM | *1/*1 | EM | *1C*1F/*1F | HI |
GS | *1/*4 | IM | *1/*1 | EM | *1/*1 | EM | *1/*2 | IM | *1/*1 | EM | *1F/*1B | UM |
GL | *1/*1 | EM | *5/*6 | IM | *1/*17 | UM | *1/*1 | EM | *1/*1 | EM | *1F/*1F | HI |
CYP2D6 | CYP2B6 | CYP2C19 | CYP2C9 | CYP3A4 | CYP1A2 | |||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
Lab | Alleles | PT | Alleles | PT | Alleles | PT | Alleles | PT | Alleles | PT | Alleles | PT |
GS | *1/*1 | EM | *1/*6 | IM | *1/*1 | EM | *1/*1 | EM | *1/*1 | EM | *1C*1D/ *1F*1B | UM |
GS | *1/*4 | IM | *1/*6 | IM | *1/*1 | EM | *1/*3 | IM | *1/*1 | EM | *1F/*1B | UM |
GS | *1/*2A | EM | *1/*6 | IM | *1/*1 | EM | *1/*1 | EM | *1/*1 | EM | *1F/*1B | UM |
GS | *1/*41 | EM | *1/*6 | IM | *1/*17 | EM | *1/*1 | EM | *1/*1 | EM | *1A*1C/ *1B | IM |
GS | *1/*4 | EM | *1/*6 | IM | *1/*1 | EM | *1/*2 | IM | *1/*1 | EM | *1D*1E/ *1F*1B | UM |
GS | *2A/*4 | EM | *1/*1 | EM | *2/*17 | EM | *1/*1 | EM | *1/*1 | EM | *1F/*1B | UM |
GS | *1/*2A | EM | *1/*6 | IM | *1/*17 | EM | *1/*1 | EM | *1/*1 | EM | *1F/*1B | UM |
GS | *10/*41 | PM | *1/*1 | EM | *1/*17 | EM | *1/*1 | EM | *1/*1 | EM | *1A/*1B | EM |
GS | *1/*5 | IM | *1/*1 | EM | *1/*1 | EM | *1/*2 | IM | *1/*1 | EM | *1F/*1B | UM |
GS | *1/*3 | IM | NA | NA | *1/*1 | EM | *1/*3 | IM | NA | NA | *1F/*1B | UM |
GS | *1/*41 | EM | *1/*6 | IM | *2/*17 | EM | *1/*1 | EM | *1/*1 | EM | *1A/*1A | EM |
GS | *4/*41 | PM | *1/*1 | EM | *1/*17 | EM | *1/*1 | EM | *1/*1 | EM | *1A/*1A | EM |
GS | *4/*41 | PM | *1/*6 | IM | *1/*1 | EM | *2/*2 | PM | *1/*1 | EM | *1F/*1B | UM |
GM | *2/*41 Dup | EM | *1/*6 | EM | *1/*1 | EM | *1/*1 | EM | *1/*22 | IM | *1A/*1F | EM |
GS | *1/*4 | IM | *1/*1 | EM | *1/*1 | EM | *1/*2 | IM | *1/*22 | IM | *1F/*1B | UM |
GL | *1/*2A | EM | *2/*5 | IM | *1/*1 | EM | *1/*2 | IM | *1/*1B | IM | *1F/*1F | HI |
CYP2D6 | CYP2B6 | CYP2C19 | CYP2C9 | CYP3A4 | CYP1A2 | |||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
Lab | Alleles | PT | Alleles | PT | Alleles | PT | Alleles | PT | Alleles | PT | Alleles | PT |
GS | *2A/*4 | EM | *1/*1 | EM | *1/*1 | EM | *1/*3 | IM | *1/*1 | EM | *1A/*1B | EM |
GS | *1/*1 | EM | *1/*1 | EM | *1/*8 | IM | *1/*2 | IM | *1/*1 | EM | *1F/*1B | UM |
GS | *1/*1 | EM | *1/*1 | EM | *1/*1 | EM | *1/*2 | IM | *1/*1 | EM | *1A/*1B | EM |
GS | *6/*41 | PM | *1/*1 | EM | *1/*17 | EM | *1/*1 | EM | *1/*1 | EM | *1F/*1B | UM |
GS | *1/*1 | EM | *1/*1 | EM | *1/*2 | IM | *1/*1 | EM | *1/*1 | EM | *1A/*1A | EM |
PWS | CYP2D6 | CYP2B6 | CYP2C19 | CYP2C9 | CYP3A4 | CYP1A2 |
---|---|---|---|---|---|---|
DEL | 4EM:8IM:2PM | 7EM:7IM | 2UM:11EM:1IM | 10EM:3IM | 12EM:2IM | 6UM:3HI:5EM |
UPD | 9EM:4IM:3PM | 6EM:9IM | 16EM | 9EM:6IM:1PM | 12EM:3IM | 10UM:1HI:4EM:1IM |
UnSpec | 4EM:1PM | 5EM | 3EM:2IM | 2EM:3IM | 5EM | 2UM:3EM |
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CYP Gene/Metabolizer Phenotype | CYP Phenotype Frequency | Substrate Frequency | |||||
---|---|---|---|---|---|---|---|
PWS Referred Cohort | Typical Population | PWS Clinic Patients | |||||
DEL | UPD | Unspec | All PWS | Frequency/Reference | NIH PWS Registry [12,13] | ||
CYP2D6 | (n = 14) | (n = 16) | (n = 5) | (n = 35) | (n = 56,945) | (n = 265) | |
EM | 28.5% † | 56.3% | 4 | 48.6% | 63.6% | http://www.pharmgkb.org/page/cyp2d6RefMaterials | Fluoxetine (21.9%), Risperidone (14%), Sertraline (14%), Aripiprazole (9.8%), Citalopram (8.7%), Escitalopram (5.7%), Paroxetine (4.5%), Bupropion (4.5%), Amphetamine (4.2%), Clonidine (3%), Ziprasidone (3%) |
IM | 57.1% * | 25.0% | 0 | 34.0% | 23.6% | ||
PM | 14.3% † | 18.8% * | 1 | 17.1% * | 2.2% | ||
CYP2B6 | (n = 14) | (n = 15) | (n = 5) | (n = 34) | (n = 56,945) | ||
EM | 50% | 40% | 5 | 53% | 43% | http://www.pharmgkb.org/page/cyp2B6RefMaterials | Sertraline (14%), Bupropion (4.5%) |
IM | 50% | 60% | 0 | 47% | 39% | ||
CYP2C19 | (n = 14) | (n = 16) | (n = 5) | (n = 35) | (n = 56,945) | ||
EM | 78.6% | 100% † | 3 | 85.7% | 76.4% | http://www.pharmgkb.org/page/cyp2C19RefMaterials | Fluoxetine (21.9%), Sertraline (14%), Citalopram (8.7%), Escitalopram (5.7%) |
IM | 7.1% | 0% † | 2 | 8.6% | 21.4% | ||
UM | 14.3% † | 0% | 0 | 5.7% | 0.74% | ||
CYP2C9 | (n = 14) | (n = 16) | (n = 5) | (n = 35) | (n = 56,945) | ||
EM | 76.9% | 56.2% * | 2 | 61.8% * | 83.2% | http://www.pharmgkb.org/page/cyp2C9RefMaterials | Fluoxetine (21.9%), Sertraline (14%), Valproate (6.4%) |
IM | 23.0% | 37.5% * | 3 | 35.3% * | 16.4% | ||
PM | 0% | 6.3% † | 0 | 2.9% | 0% | ||
CYP3A4 | (n = 14) | (n = 15) | (n = 5) | (n = 34) | (n = 5789) | ||
EM | 85.7% † | 80.0% † | 5 | 85.3% * | 97.3% | Zhou et al., 2017 [20] | Risperidone (14%), Sertraline (14%), Modafinil (12.8%), Aripiprazole (9.8%), Citalopram (8.7%), Clonazepam (6.8%), Escitalopram (5.7%), Bupropion (4.5%), Ziprasidone (3%) |
IM | 14.3% † | 20.0% † | 0 | 14.7% * | 2.7% | ||
CYP1A2 | (n = 14) | (n = 16) | (n = 5) | (n = 35) | (n = 183) | ||
UM | 42.9% * | 62.5% * | 2 | 51.4% * | 0% | Muscat et al., 2008 [27] | Fluvoxamine (1.1%), Haloperidol (1.1%), Thioridazine (1.1%), Olanzapine (0.4%), Chlorpromazine (0.4%), Imipramine (0.4%) |
EM/HI | 57.1% | 31.2% | 3 | 45.7% | 37.0% | ||
IM | 0% † | 6.25% † | 0 | 2.85% | 54.0% | ||
PM | 0% | 0% | 0 | 0% † | 10.0% |
Cytochrome | CYP1A2 | CYP2B6 | CYP2C19 | CYP2C9 | CYP2D6 | CYP3A4-5 |
---|---|---|---|---|---|---|
Substrate | Acetaminophen Amitriptyline, 3 Benztropine, 2 Caffeine Cannabidiol, 3 Chlorpromazine, 2 Clomipramine, 2 Clozapine, 1 Duloxetine, 1 Estradiol Fluvoxamine, 1 Haloperidol, 3 Imipramine, 2 Melatonin Mirtazapine, 3 Olanzapine, 1 Pimozide Propranolol, 1 Tacrine Thioridazine, 2 | Bupropion, 1 Selegiline Sertraline, 1 Sibutramine | Amitriptyline, 1 Benztropine, 3 Cannabis, 1 Cannabidiol, 2 Citalopram, 1 Clomipramine, 1 Clozapine, 2 Diazepam Doxepin, 2 Escitalopram, 1 Estradiol Fluoxetine,3 Imipramine, 1 Nortriptyline, 2 Omeprazole Phenytoin Progesterone, 1 Sertraline, 2 Testosterone, 1 Venlafaxine, 2 | Amitriptyline, 2 Benztropine, 4 Cannabidiol, 3 Cannabis, 3 Celecoxib Fluoxetine, 2 Ibuprofen, 1 Progesterone, 2 Sertraline, 3 Valproate Warfarin | Amitriptyline, 2 Amphetamine Aripiprazole, 2 Asenapine Atomoxetine Bupropion, 2 Cannabidiol, 3 Chlorpromazine, 1 Citalopram, 3 Clomipramine, 4 Clonidine Clozapine, 3 Desipramine, 4 Dextromethorphan Diphenhydramine Doxepin, 1 Escitalopram, 3 Fluoxetine, 1 Fluvoxamine, 2 Haloperidol, 1 Hydroxyzine Imipramine, 2 Mirtazapine, 2 Nortriptyline, 1 Olanzapine, 2 Paroxetine, 1 Perphenazine Propranolol, 2 Quetiapine, 2 Ranitidine Risperidone, 1 Sertraline, 2 Thioridazine, 1 Trazadone, 2 Venlafaxine, 1 Ziprasidone, 3 | Alprazolam Aripiprazole, 1 Benztropine, 1 Bupropion, 2 Buspirone Cannabis, 2 Cannabidiol, 1 Cisapride Citalopram, 2 Clomipramine, 3 Clonazepam Carbamazepine Desvenlafaxine Dextromethorphan Duloxetine, 3 Escitalopram, 2 Estradiol Erythromycin Fexofenadine Guanfacine Haloperidol, 2 Loratadine Lurasidone Mirtazapine, 1 Modafinil Pimozide Progesterone, 3 Quetiapine, 1 Risperidone, 2 Sertraline, 3 Testosterone Trazadone, 1 Tiagabine Ziprasidone, 1 Zolpidem |
Inhibitor | Cannabidiol Cannabis Celecoxib Cimetidine Citalopram Ciprofloxacin Clarithromycin Erythromycin Estradiol Fluvoxamine Isoniazid Ketoconazole Modafinil | Cannabidiol Cannabis | Cannabidiol Cannabis Cimetidine Contraceptives Fluconazole Fluoxetine Fluvoxamine Indomethacin Isoniazid Ketoconazole Lansoprazole Modafinil Omeprazole Oxcarbazepine Probenecid Topiramate | Cannabidiol Cannabis Cimetidine Contraceptives Fluconazole Fluoxetine Fluvoxamine Isoniazid Ketoconazole Methylphenidate Modafinil Omeprazole Paroxetine Sertraline Sulfonamides Tacrine | Asenapine Bupropion Cannabis Cannabidiol Diphenhydramine Fluoxetine Goldenseal Haloperidol Hydroxyzine Methylphenidate Paroxetine Propranolol Quinidine Ranitidine | Cannabidiol Cimetidine Ciprofloxacin Clarithromycin Cyclosporine Erythromycin Goldenseal Grapefruit juice Isoniazid Ketoconazole Prednisone Sertraline Verapamil |
Inducer | Carbamazepine Cruciferous vegetables Cannabis (smoke) Char-grilling Omeprazole Phenytoin St. John’s wort Tobacco (smoke) | Carbamazepine Modafinil Phenytoin Phenobarbital Rifampin | Rifampin | Carbamazepine Phenobarbital Rifampin St. John’s wort | Carbamazepine Cruciferous vegetables Ginseng Modafinil Phenytoin Rifampin St. John’s wort |
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Forster, J.; Duis, J.; Butler, M.G. Pharmacogenetic Testing of Cytochrome P450 Drug Metabolizing Enzymes in a Case Series of Patients with Prader-Willi Syndrome. Genes 2021, 12, 152. https://doi.org/10.3390/genes12020152
Forster J, Duis J, Butler MG. Pharmacogenetic Testing of Cytochrome P450 Drug Metabolizing Enzymes in a Case Series of Patients with Prader-Willi Syndrome. Genes. 2021; 12(2):152. https://doi.org/10.3390/genes12020152
Chicago/Turabian StyleForster, Janice, Jessica Duis, and Merlin G. Butler. 2021. "Pharmacogenetic Testing of Cytochrome P450 Drug Metabolizing Enzymes in a Case Series of Patients with Prader-Willi Syndrome" Genes 12, no. 2: 152. https://doi.org/10.3390/genes12020152