Lecture 9

Question 1

How might toxic effects slip through clinical trials?

Answer 1

Non-response from patients experiencing the toxic effect.

Question 2

Factors Affecting ADME

Answer 2

• Gender
• Age
• Weight
• Fitness
• Diet
• Organ function
• Other medicines
• Lifestyle
• Other health states
• Genetics

Some are not evident until after the drug is taken, can have significant effects on drugs like increasing half lives

Question 3

PK alters….

Answer 3

Levels and durations of drugs in the body

• Increased serum levels/duration will increase the likelihood of adverse effects
• Decreased serum levels/durations will decrease the clinical response

Question 4

PK Examples

Answer 4

• GI Absorption altered - disease status of food
• Distribution/Transport - differences in non-receptor drug binding sites in plasma or tissues, Vd or obesity
• Excretion - renal or hepatic function due to age or disease process

Question 5

Differences in Metabolism

Answer 5

Metabolic enzymes may be regulated by:

• Non-genetic change in enzyme activity (diet, drugs, etc.)
• Genetic variations - polymorphisms

Question 6

Non-Genetic Changes

Answer 6

• Environmental or lifestyle expose introduces a chemical (natural or synthetic) that modifies enzymatic activity
• Can modify enzyme activity via competition or induction

Question 7

Importance of CYP3A4

Answer 7

• About half of all drugs are metabolized by this enzyme in Phase I
• Includes statins, alprazolam, loratidine, warfarin, and methadone
• Grapefruit is an inhibitor of this enzyme

Question 8

Genetic Modifications

Answer 8

• Twin studies have shown that drug metabolism is increasingly seen as heritable
• Many genetic factors account for most of the variations in metabolic rates for many drugs

Question 9

Polymorphism

Answer 9

• DNA variation that occurs with >1% frequency
• Can occur in coding or non-coding regions
• May be insetions or deletions
• May be point mutations, can be synonymous (no change in amino acid) or nonsynonymous (change in amino acid)

Question 10

Important Genetic Polymorphisms

Answer 10

• Isoniazid (acetylation) NAT2 - slow acetylation phenotype, increases the ADR
• Warfarin (hydroxylation) CYP2C9 - Polymorphism that increases the bleeding risk
• Codeine (oxidation) CYP2D6 - Increase or decrease in metabolism depending on the polymorphism
• Omeprazole (O-demethylation) CYP2C19 - poor metabolizers that increases the efficacy

Question 11

Impact varies based on Therapeutic Window

Answer 11

• CYP29*3 variant - Warfarin clearence is about 10% of normal values which causes a BIG bleeding risk
• Same variant also affects metabolisms of certain nonsteroidal anti-inflammatory drugs that are less critical concerns

Question 12

Why does this matter?

Answer 12

• 40% of human P450-mediated drug metabolism is by polymorphic CYP isozymes
• Polymorphisms can alter “effective” doses (ADR and drug interactions)
• Inter-individual variation in human metabolism is an obstacle to new drug development and may account for 30-40% of failures in clinical trials

Question 13

Transporter Variation

Answer 13

• Drug transporter P-glycoprotein (MDR-1, ABCB1) affects response to cancer, viral, histamine, convulsion, and immunosuppressant drugs
• P-glycoproteins are also is associated with tacrolimus and nortriptyline neurotoxicity and susceptiblility to developing ulcerative colitis, renal carcinoma, and Parkinson’s disease
• Transporter variation can also affect levels of drug targets in the body (EX: Methotrexate’s DHFR)