Via Research Recognition Day 2024 VCOM-Carolinas

Biomedical Studies

Barbiturate Metabolism and Their Known Genetic Associations: Present Understandings and Prospective Paths Cristin Grant, OMS-III, Steven Enkemann, PhD Edward Via College of Osteopathic Medicine, Spartanburg, South Carolina

Abstract

Results

Summary

Genetic Impact on Medication Metabolism v Barbiturate Induction of CYP3A4 12 :

Enzymes v Limited information is available about the metabolism of barbiturates. v Among the frequently utilized barbiturates, only amobarbital has identified enzymes associated with its metabolism. v Barbiturates induce numerous CYP enzymes, with phenobarbital being one of the few commonly used ones that also induces UGT enzymes.

Context : Barbiturates were developed well before the era of personalized medicine and are less commonly used today. For this reason, much of the standard analysis of drug metabolism has not been systematically investigated. Yet, genetic information about barbiturate metabolism could mitigate side effects, reduce cases of abuse, and optimize drug management. Objective : To ascertain the extent of knowledge concerning enzymes involved in barbiturate pharmacokinetics and the role genetic variation may play in barbiturate pharmacotherapy. Methods : A review of current barbiturate medications utilized in the United States was conducted and these medications were analyzed by indication, mechanism of action, and enzymes involved in metabolism. Additionally, a search was conducted to investigate genetic variations associated with these medications. Results : For most barbiturates there is little knowledge of the metabolism and how human variation might influence activity and adverse events. Amobarbital was the only barbiturate with extensive research regarding enzymes that are directly involved in its metabolism. Amobarbital is glucuronidated by UGT1A3, UGT1A1, and UGT1A4, as well as glucosidated by UGT2B4, UGT2B7, and UGT2B15. Research also suggests that all barbiturates currently in use are likely both hepatically metabolized by CYP3A4 and induce the enzyme as well. Secobarbital and phenobarbital were found to be inducers of other CYP enzymes as well. Secobarbital induces CYP1A2, CYP2C8, CYP2C9, CYP2C19, and CYP3A4 while phenobarbital induces CYP2A CYP2B, CYP2C, CYP3A, CYP2E1, UGT1A6, UGT1A10, UGT2B4, UGT2B15, and UGT2B17. Conclusion : Despite similar chemical structures, limited knowledge exists about the metabolism of barbiturates. Further work is required to understand which liver enzymes work on each barbiturate, and how they further influence liver metabolism. With this knowledge, the medical field can better understand how human variation affects both desirable and undesirable activities of barbiturates.

• Barbiturate enzymes induce CYP3A4, heightening metabolism. • Reduced effectiveness of medications processed by CYP3A4. • Essential to consider dosage adjustments when prescribing interacting medications. v Secobarbital's Broad CYP Enzyme Induction 5 : • Secobarbital induces 5 known CYP enzymes and may accelerate metabolism of medications via this pathway. v Phenobarbital's Diverse Enzyme Induction 14,15 : • Phenobarbital induces 5 known CYP and 6 known UGT enzymes and may accelerate metabolism of medications via this pathway. v Amobarbital Metabolism 13 : • Amobarbital is glucuronidated by UGT1A3, UGT1A1, and UGT1A4 and glucosidated by UGT2B4, UGT2B7, and UGT2B15. UGT2B15 Enzyme and Genetic Polymorphisms v UGT2B15 and Medication Metabolism 13,15,16 : • UGT2B15 interacts with both phenobarbital and amobarbital. • Phenobarbital induces this enzyme, while amobarbital is glucosidated by it. • Clinically significant UGT2B15*2 allele linked to reduced clearance of lorazepam and oxazepam. v UGT2B15 D85Y Polymorphism 17 : • UGT2B15 D85Y polymorphism decreases the risk of prostate cancer. • Metabolizes dihydrotestosterone, associated with prostate cancer progression. Implications for Clinical Practice and Future Research v Clinical Insights and Therapeutic Considerations: • Research on phenobarbital and amobarbital metabolism offers insights for prescribing lorazepam and oxazepam. 16 • Exploration of genetic polymorphisms may enhance their utility in oncology management. 17 v Limited Knowledge on Barbiturate Metabolism: • Barbiturates share a comparable chemical structure, but limited knowledge exists regarding their metabolic processes. 5 • Research regarding the specific CYP isoforms induced by barbiturates appears to be incomplete. Most notably, there is very limited evidence regarding the specific CYP isoforms induced by phenobarbital. • Understanding drug metabolism is pivotal for predicting variations in drug responses. • Further research is essential to comprehensively grasp the clinical implications of these enzymes and maximize their application in personalized medicine.

Table 2. Barbiturates and the enzymes they induce and the enzymes that are directly involved in their metabolism.

Background

Cytochrome P450 v The relative distribution of the CYP enzyme families induced by the barbiturates analyzed v All commonly used barbiturates serve as inducers of CYP enzymes, with CYP3A4 being the most frequently affected enzyme.

Current State of Barbiturate Use: • Use declining due to their high potential for abuse. 3 • Most used today: amobarbital, secobarbital, butalbital, methohexital, and phenobarbital. 4 • Currently barbiturates are not commonly used as first line treatment options due to their wide array of adverse effects. 4

History of Barbiturates: • Widely used for over 100 years. 1 • Synthesized by Adolf von Baeyer in 1864 and remodified by Edouard Grimaux in 1879. 2 • Mostly used for their depressive and sedative effects. 2

References

Methods: LitVar and DrugBank databases were used to identify enzymes induced by each barbiturate. LitVar was then utilized to identify any known genetic variants that influence enzymes involved.

1. Cozanitis DA. One Hundred Years of Barbiturates and Their Saint. J R Soc Med . 2004;97(12):594-598. doi:10.1177/014107680409701214 2. López-Muñoz F, Ucha-Udabe R, Alamo C. The history of barbiturates a century after their clinical introduction. 3. Sarrecchia C, Sordillo P, Conte G, Rocchi G. [Barbiturate withdrawal syndrome: a case associated with the abuse of a headache medication]. Ann Ital Med Interna Organo Uff Della Soc Ital Med Interna . 1998;13(4):237-239. 4. Skibiski J, Abdijadid S. Barbiturates. In: StatPearls . StatPearls Publishing; 2023. Accessed October 14, 2023. http://www.ncbi.nlm.nih.gov/books/NBK539731/

Figure 1. Illustrates the relative distribution of different CYP enzyme families so far demonstrated to be induced by the most commonly used barbiturates in the United States. 5,12,14 Only the CYP3A family seems to be induced by many barbiturates.

5. DrugBank Online. Drug bank. Accessed October 14, 2023. https://go.drugbank.com/unearth/q?query=barbiturates&button=&searcher=drugs 6. Syed Q, Kohli A. Methohexital. In: StatPearls . StatPearls Publishing; 2023. Accessed October 14, 2023. http://www.ncbi.nlm.nih.gov/books/NBK544291/ 7. DEA Diversion Control Division. Controlled Substances. Accessed October 14, 2023. https://www.deadiversion.usdoj.gov/

Barbiturate Overview v Most major barbiturates are similar in structure and should likely have overlap in their metabolism.

8. Kales A, Hauri P, Bixler EO, Silberfarb P. Effectiveness of intermediate-term use of secobarbital. Clin Pharmacol Ther . 1976;20(5):541-545. doi:10.1002/cpt1976205541 9. Silberstein SD, McCrory DC. Butalbital in the Treatment of Headache: History, Pharmacology, and Efficacy. Headache J Head Face Pain . 2001;41(10):953-967. doi:10.1046/j.1526- 4610.2001.01189.x 10. Alvarez N. Barbiturates in the treatment of epilepsy in people with intellectual disability. J Intellect Disabil Res JIDR . 1998;42 Suppl 1:16-23. 11. Lewis CB, Adams N. Phenobarbital. In: StatPearls . StatPearls Publishing; 2023. Accessed October 14, 2023. http://www.ncbi.nlm.nih.gov/books/NBK532277/ 12. Kim BH, Fulco AJ. Induction by barbiturates of a cytochrome P-450-dependent fatty acid monooxygenase in Bacillus Megaterium: Relationship between barbiturate structure and inducer activity. Biochem Biophys Res Commun . 1983;116(3):843-850. doi:10.1016/S0006-291X(83)80219-8 13. Kenji Toidea, Yoshiaki Terauchib, Toshihiko Fujiib, Hiroshi Yamazakia, Tetsuya Kamatakia. Uridine diphosphate sugar-selective conjugation of an aldose reductase inhibitor (AS-3201) by UDP glucuronosyltransferase 2B subfamily in human liver microsomes. Published online November 12, 2003. 14. Cantiello M, Carletti M, Giantin M, et al. Induction by Phenobarbital of Phase I and II Xenobiotic-Metabolizing Enzymes in Bovine Liver: An Overall Catalytic and Immunochemical Characterization. Int J Mol Sci . 2022;23(7):3564. doi:10.3390/ijms23073564 15. Plummer S, Beaumont B, Elcombe M, et al. Species differences in phenobarbital-mediated UGT gene induction in rat and human liver microtissues. Toxicol Rep . 2021;8:155-161. doi:10.1016/j.toxrep.2020.12.019 16. Guillemette, Chantal (Director) Ph.D. Pharmacogenomics Laboratory. https://www.pharmacogenomics.pha.ulaval.ca 17. Zhong X, Feng J, Xiao Y, et al. Uridine diphosphate-glucuronosyltransferase 2B15 D85Y gene polymorphism is associated with lower prostate cancer risk: a systematic review and meta-analysis. Oncotarget . 2017;8(32):52837-52845. doi:10.18632/oncotarget.17375 18. Sedative-hypnotic and anxiolytic drugs . Basicmedical Key. (2017, January 1). https://basicmedicalkey.com/sedative-hypnotic-and-anxiolytic-drugs-2/ We wish to acknowledge our appreciation for the valuable assistance provided by the Library Staff at the Carolinas Campus in obtaining difficult to find manuscripts. Acknowledgements

UGT2B15 v UGT2B15, has been identified to possess a corresponding allele and genetic polymorphism. v This enzyme plays a direct role in the metabolism of amobarbital and is induced by phenobarbital. v The found clinical implications of this enzyme are listed below.

Table 1. Most used barbiturates in the United States, mechanism of action, chemical comparison, and most common indications for use.

Table 3. The UGT2B15 enzyme and the role it plays in barbiturate metabolism and the known allele and polymorphism, along with their corresponding clinical implications.

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