Current View towards Pharmacokinetics in Drug Discovery

**71**

**Chapter 5**

**Abstract**

were also assessed.

**1. Introduction**

pharmacogenetics, stereoselectivity

Revisiting Pharmacokinetics and

Pharmacogenetics of Methadone

*Pietro Fagiolino, Iris Feria-Romero and Sandra Orozco-Suarez*

Methadone acts as a μ opioid agonist, a serotonin and norepinephrine reuptake inhibitor, and a noncompetitive N-methyl-D-aspartate receptor antagonist. These actions altogether are responsible for its efficacy in the management of chronic pain. It is available as a racemic mixture of (R)- and (S)-methadone, both being stereoisomers responsible for its analgesic effect. Methadone elimination occurs mainly through metabolism in the liver by CYP3A4, CYP2B6, and CY2C19 and to a lesser extent by CYP2D6 and in the intestine by CYP3A4. The relative intestinal content of CYP2B6 and CY2C19 is unknown but it seems that CYP2B6 is not present at the intestine. CYP3A4, CYP2B6, and CYP2C19 convert methadone mainly into 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine(EDDP). CYP2B6 and CYP2C19 are stereoselective to S- and R-enantiomer, respectively. The pharmacokinetic study carried out in healthy volunteers by our research group confirmed that MTD undergoes recirculation via gastric secretion and intestinal reabsorption and revealed that the drug is extensively metabolized in the liver but intestinal metabolism is not only relevant but also stereoselective. Polymorphisms of the CYP2B6 and CYP2C19 isoenzymes and their relationship with the pharmacokinetics of MTD

**Keywords:** methadone stereoisomers, EDDP stereoisomers, pharmacokinetics,

Methadone (MTD) is a synthetic opioid with primarily a μ and δ opioid agonist action, but some other novel mechanisms implied in pain relief such as antagonism of the N-methyl-D-aspartate (NMDA) receptor, and inhibition of serotonin and norepinephrine reuptake are also reported in the literature [1–5]. These multiple receptor activities make it an attractive choice for analgesia. It is increasingly used to manage cancer and chronic nonmalignant pain [6, 7] and although some authors stated its use in neuropathic pain as well, [3, 8, 9] good evidence for this use is still lacking [10]. NMDA antagonism has an important role in attenuating tolerance [11]. In comparison to oral morphine and other opioids, MTD has a higher bioavailability and initial rapid and extensive distribution and a slower elimination rate.

*Natalia Guevara, Marianela Lorier, Marta Vázquez,* 

in Healthy Volunteers

## **Chapter 5**
