pharmacogenomics- mitsouras Flashcards
define pharmacokinetics (PK), pharmacodynamics (PD)
Pharmacokinetics (PK)=> the study of the time course of drugs and their relationship with an organism or system (availability of drug in body)
PK encompasses drug absorption, distribution, metabolism & excretion
Pharmacodynamics (PD) => the study of the biochemical and physiological effects of drugs, the mechanisms of drug action and the relationship between drug concentration & effect (drug effect on the body)
PD encompasses interaction of drug with receptors, transporters and enzymes
variation in PK and PD affects 1. drug efficacy and 2. ADRs (drug toxicity)
what is the function of TPMT and how do SNPs affect its activity?
6-mercaptopurine is a chemotherapeutic used to treat ALL
6-MP Incorporates into DNA/ RNA of tumor cells & causes cytotoxicity
6-MP is inactivated by thiopurine methyltransferase (TPMT)
TPMT activity can be measured in RBCs from patient
SNPs in TPMT affect enzyme activity & ability to inactivate 6-MP
Low/ no TPMT activity => inability to inactivate 6-MP & severe toxicity of 6-MP
** TPMT *2, *3A & *3C alleles have low TPMT activity
Homozygotes for low activity TPMT alleles are at high risk for drug-induced toxicity
how do CYP2D6/CYP2C19 affect drug metabolism?
CYP2D6 & CYP2C19 are members of P450 family of cytochromes
Involved in drug metabolism in liver =>affect how well drug reaches therapeutic level & how well drug is cleared
Metabolize 25% of all therapeutic drugs, 50 of the 100 best selling drugs
Genetic variation in CYP2D6 & CYP2C19 gives rise to alleles with different levels of enzyme activity & different metabolic phenotypes for drugs
1) Extensive metabolizers (normal enzyme activity & metabolism)
2) Intermediate metabolizers (reduced activity & slower than normal metabolism)
3) Poor metabolizers (no activity & almost no metabolism)
4) Ultrarapid metabolizers (higher than normal activity & faster than normal metabolism)
ex: codeine is a pro-drug. must be converted to morphine by CYP2D6 for its effect
- and ultrarapid metabolizer can have higher than normal levels of morphine
- poor metabolizer will have low levels of morphine–> will need more than normal to achieve pain relief
How will the different CYP450 phenotypes affect the metabolism of non pro-drugs?
o Extensive metabolizers • Normal metabolism • Expected response at standard dosage. o Intermediate metabolizers • Slower than normal metabolism. • May experience some or a lesser degree of the consequences of poor metabolizers. o Poor metabolizers • Too slow or no metabolism. • Too high drug levels at standard dose. • High risk for adverse reactions and side effects. o Ultrarapid metabolizers • Faster than normal metabolism • No response at standard dosage (non-responder)
How will the different CYP450 phenotypes affect the metabolism of pro-drugs?
o Extensive metabolizers • Normal metabolism • Expected response at standard dosage. o Intermediate metabolizers • Slower than normal metabolism. • May experience some or a lesser degree of the consequences of poor metabolizers. o Poor metabolizers • Too slow or no metabolism. • No response at standard dosage (non-responder). o Ultrarapid metabolizers • Faster than normal metabolism. • Too high drug levels at standard dose. • High risk for adverse reactions and side effects.
