ASAM Annual Conference 2015, Austin, TX

M.P. George

Chief Toxicologist, VP Laboratory Operations and Innovation Alere Toxicology

ASAM Disclosure of Relevant Financial Relationships

Content of Activity:

Name Commercial Interests

Relevant Financial

Relationships: What Was Received

Relevant Financial

Relationships: For What Role

No Relevant Financial

Relationships with Any

Commercial Interests

M.P. George Alere Toxicology Salary and stock options

Full Time Employee

Drugs and chemicals are metabolized by the human body to eliminate them

Genetic variants affect the drug metabolism

Physicians’ understanding of the polymorphisms: Predict the response to the drugs

Better efficacy

Reduce adverse drug interactions

Better cost-benefit ratio

Oral Dose Stomach 100% Dose

Gut

Lever Blood

70%

15%

Phase I Phase II

Phase I Phase II

Phase I Metabolism Phase II Metabolism

Polymorphic enzyme cytochrome 450 (CYP---)

Purpose is to make more polar for water solubility and Phase II metabolism

Polymorphic enzyme vary based on the genotype of the human body

Drugs and chemicals could:

Inhibit the enzyme or induce the enzyme activity

Terminate the pharmacological effect of the drug

Make the molecule so water soluble

Glucuronidation is the process human body uses to clear the drugs

A set of enzymes called urindine diphospahte glucuronosyl transferases (UGTs)

Liver is primary organ for glucuronidation and gut and kidney also have the enzymes.

Example I:

CYP Morphine Normorphine

UGT UGT

Glucuronide and Sulphate conjugates

Example 2

Hydrocodone CYP3A4 Norhydrocodone Hydromorphone CYP 2D6

Hydromorphone-3-glucuronide

UGT2B7 UGT1A3

Inducers of CYP2D6 diminish the potency by forming weaker metabolite

Inhibitors of CYP2D6 would accumulate the parent drug

Pill scraping can be eliminated with the presence of norhydrocodone on people with CYP 2D6 deficiency

Example 3

Oxycodone Noroxycodone Oxymorphone

Oxymorphone-3- glucuronide

UGT 2B7 UGT 1A3

CYP2D6 CYP3A4

Inducers of CYP2D6 diminish the potency by forming weaker metabolite Inhibitors of CYP2D6 would accumulate the parent drug

Pill scraping can be eliminated with the presence of noroxycodone on people with CYP2D6 deficiency

Drug is poorly absorbed

Drug is only effective when the level reaches its therapeutic concentration

Drugs failure:

1. Poorly absorbed

2. Drug is metabolized too fast due to pharmacodynamics

Drug failure can occur when a new drug or chemical is taken and this is usually a gradual process and can take days before detecting it.

Overdose

Failure of drug removal

Hepatic insufficiency

Polymorphism or genetic variants

Other drugs or chemical induced pharmacodynamics change

Sample

Plus

Isotopic Deuterium labeled Internal Standards

Hydrolyze to break the

glucuronide bond to free drug

Sample Isolation Inject into

LC-MS/MS

Sample preparation or isolation for LC-MS/MS takes hours

Urine specimens must be hydrolyzed prior to analysis

Thank you. Questions?

M.P. George Chief Toxicologist, VP Laboratory Operations and Innovation Alere Toxicology

Email: m.p.george@alere.com

www.aleretoxicology.com