In vitro and in vivo studies of methadone metabolism and pharmacokinetics
Dinh, Jean Chinh
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Methadone ((R,S)-6-dimethylamino-4, 4-diphenyl-3-heptanone) is a synthetic mu-opioid receptor agonist developed in Germany during World War II as a replacement for morphine. Methadone is currently used to aid in opioid cessation and chronic pain control; two ailments that require indefinite drug therapy. While the drug is certainly beneficial to many patients, severe and sometimes fatal adverse events overshadow its usage. In the years between 2000-2009 methadone prescriptions have increased as have the number of unique patients using the medication. Unfortunately trending with this increase in prescription number are the casualties caused by methadone overdose. Currently, an effective prediction and prevention strategy for methadone toxicity remains elusive. This is partially due to high inter-individual variability in the efficacy and toxicity of the drug. Further studies investigating factors that influence variability are necessary to make methadone a safer and more effective medication. The purpose of this dissertation project is to explore the roles of cytochrome P450 (CYP) enzymes and permeable-glycoprotein (P-gp), an efflux transporter, in the metabolism and disposition of methadone. Previous research focused on CYP3A4, CYP2B6, and P-gp proteins as potential contributors to the overall pharmacokinetic profile of methadone mainly because; 1) methadone is a substrate for each of these proteins and 2) in vivo activities of aforementioned proteins are highly variable among individuals. CYP3A4, the most abundant CYP in the liver and gastrointestinal tract, is the major P450 enzyme responsible for the metabolism and clearance of a large number of xenobiotics. It is known to metabolize methadone in vitro but its contribution to in vivo clearance has been questioned. CYP2B6 has long been considered a minor player among the CYP super-family, although recent evidence suggest that its role is underestimated due to high substrate overlap and similar regulation pathways with CYP3A4. Interest in CYP2B6 has increased in recent years because of its highly polymorphic nature and several allelic variants have been shown to be clinically relevant in efavirenz therapy. P-gp, an ATP-catalyzed efflux transporter is also highly polymorphic and capable of effluxing numerous compounds of various structures and therapeutic classes. P-gp is expressed in the gastro-intestinal tract, kidneys, and along several blood-tissue barriers. Mutations in ABCB1, the gene that encodes for P-gp, is thought to lead to variable expression and activity of the protein. Changes in P-gp activity could, therefore, influence methadone drug exposure. This project encompasses in vitro and in vivo investigations to determine the relative contribution of each protein to methadone metabolism and clearance. A better understanding of factors that underlie methadone's variability will be crucial to improve clinical safety and better predict adverse drug effects.
- Medicinal chemistry