Clinical Trials, Biotransformation, Pharmacogenomics

Question 1

A ____ is an inactive drug that undergoes biotransformation to become an active drug. This mostly occurs in the ____ at some point between absorption and general circulation

Answer 1

Prodrug; liver

Question 2

As a general rule:

_____ reactions result in biological inactivation of the drug and are catabolic

_____ reactions produce a metabolite with improved water solubility and increased molecular weight (enhances elimination); anabolic

Answer 2

Phase I

Phase II

Question 3

Phase I enzymes are located in the lipophilic ____membranes of the liver and other tissues

Answer 3

ER

Question 4

What are some well characterized inducers of CYP450 enzymes?

Answer 4

Phenytoin (anticonvulsant)
Phenobarbital
Chronic ethanol (CYP2E1)
Aromatic hydrocarbons (benzoapyrene) - tobacco
Rifampin (anti-Tb)
St. Johns wort

Question 5

Well known inhibitor of CYP450

Answer 5

Grapefruit juice (consumption can irreversibly inhibit intestinal CYP3A4)

Mercaptopurine (coadministration with allopurinol prolongs the duration of mercaptopurine action and enhances its chemotherapeutic and toxic effects)

Question 6

How can acetaminophen lead to hepatotoxicity

Answer 6

When acetaminophen intake exceeds therapeutic doses: glucuronidation and sulfation pathways are saturated and P450 pathways become increasingly important

Over time, hepatic GSH is depleted faster than it is regenerated. Toxic metabolites accumulate resulting in hepatotoxicity

Alcohol consumption has similar effect

Question 7

Most common disease-producing enzyme defect of humans

Answer 7

G6PD deficiency

Question 8

Ryanodine receptor mutations may cause a reaction to inhalational anesthetics and succinylcholine having what effect?

Answer 8

Elevation of calcium in sarcoplasm of muscle leads to muscle rigidity, elevation of body temp, and rhabdomyelosis

[malignant hypothermia]

Question 9

What type of test usually involves 2 species, 2 routes, determines the no-effect dose and the maximum tolerated dose

Answer 9

Acute toxicity

Question 10

What type of test involves 3 doses and 2 species, allowing 2 weeks to 3 months of testing before clinical trial in order to determine biochemical and physiologic effects

Answer 10

Subacute or subchronic toxicity test

Question 11

What type of test involves rodent and nonrodent species for at least 6 months and is required when a drug is intended to be used in humans for prolonged periods?

Can this be run concurrently with clinical trials?

Answer 11

Chronic toxicity; usually run concurrently with clinical trials

Question 12

Describe testing for carcinogenic potential

Answer 12

2 years, 2 species; required when drug is intended to be used in humans for prolonged periods; determines gross and histologic pathology

Question 13

Describe testing for mutagenic potential

Answer 13

Test effects on genetic stability and mutations in bacteria (ames test) or mammalian cells in culture; dominant lethal tesst and clastogenicity in mice

Question 14

Describe testing for investigative toxicology

Answer 14

Determine sequence of mechanisms of toxic action. Discover genes, proteins, paths involved; develop new methods for assessing toxicity

Question 15

Most abundantly expressed CYP450 enzyme, involved in metabolism of about 50% of clinically used drugs

Answer 15

CYP3A4

Question 16

Individuals with genetic defects in pseudocholinesterase can metabolize ____ at 50% the rate as normal individuals

Answer 16

Succinylcholine

Question 17

Individuals with the AR ____ ____ phenotype have a decrease in N-acetyltransferase levels in the liver

What is the result?

Answer 17

Slow acetylator

As a result, isoniazid, hydralazine, caffeine, and other amines are metabolized at slower rates which can lead to hepatotoxicity

Question 18

For drugs whose biotransformation is flow-limited, cardiac disease may cause specific drug levels to rise

What are some drugs in which this is the case?

Answer 18

Atenolol and propranalol

Isoniazid

Lidocaine

Morphine

Verapamil

Question 19

Enzyme responsible for O-demethylation conversion of codeine into morphine to produce desired analgesic effect

Thus polymorphisms in this gene cause pt to experience insufficient pain relief, due to higher systemic concentrations of morphine

Answer 19

CYP2D6

[involved in metabolism of up to 1/4 of all drugs used clinically, including predominantly basic compounds such as beta blockers, antidepressants, antipsychotics, and opioid analgesics]

Question 20

Enzyme responsible for conversion of clopidogrel to the active thiol metabolite responsible for antiplatelet activity

Thus when polymorphisms are present = decrease active metabolite formation and consequently reduce drug antiplatelet activity

Answer 20

CYP2C19

[known to preferentially metabolize acidic drugs including PPIs, antidepressants, antiepileptics, and antiplatelet drugs)

Question 21

Complete or partial deficiency of this enzyme can lead to dramatically reduced clearance of 5-FU, increased levels of toxic metabolites 5-FUMP and 5-FdUMP, and consequently an increased risk for severe dose-dependent fluoropyrimidine-based chemo

Answer 21

DPD, encoded by DPYD gene

[RL step in pyrimidine catabolism and major elimination route for fluoropyrimidine chemotherapy]

This is a phase I enzyme

Question 22

Phase II enzyme that when deficient can lead to increased risk of severe life-threatening toxicities — neutropenia, and diarrhea — due to decreased clearance of SN-38 (cytotoxic metabolite of irinotecan chemotherapeutic agent)

Answer 22

UGT1A1

Question 23

Enzyme involved in phase II metabolism of azathioprine, 6-MP, and 6-TG such that polymorphisms may increase risk of exposure to cytotoxic 6-TGN metabolites and thiopurine-related toxicities

Answer 23

TPMT

Question 24

Individuals with _____ enzyme deficiency receiving rasburicase therapy are at greatly increased risk for severe hemolytic anemia and methemoglobinemia

Answer 24

G6PD

Question 25

The ______ transporter, encoded by the SLCO1B1 gene, is located on the sinusoidal membrane of hepatocytes and is responsible for hepatic uptake of mainly weakly acidic drugs and endogenous compounds (e.g., statins, methotrexate, and bilirubin)

Answer 25

OATP1B1

[mutations/polymorphisms lead to myopathy/skeletal m. toxicity]

Question 26

___ = efflux transporter in ATP binding cassette superfamily located on epithelial cells of kidney, liver, and intestine as well as endothelial cells of BBB, associated with changes in response to allopurinol and rosuvastatin as well as toxicity to various anticancer drugs

Answer 26

BCRP

Question 27

Drug-induced hypersensitivity reactions are now being assessed in clinical trials in what way?

Answer 27

Testing for HLA-B*5701 — contributes to immunogenicity to certain drugs like abacavir

Question 28

The effects of 2 genes: ____ and ____ affect dose requirement of warfarin

Answer 28

CYP2C9; VKORC1

[polymorphisms lead to reduction in warfarin metabolism, bleeding disorders, and increased sensitivity to warfarin]

Question 29

Phase 0 in clinical trial

Answer 29

Microdosing of prospective drug candidates are administered to human volunteers

provide early pharmacokinetic data, and only require minimal preclinical toxicology safety testing

Used in situations where traditional methods like in vitro and lab animal models prove unreliable

Financially advantageous

Question 30

Phase I in clinical trials

Answer 30

Determines whether humans and animals show significantly different responses to investigational drug and establish probable limits of safe clinical dosage range

Small number of healthy volunteers (25-50) — unless drug may produce toxicity like in AIDS and cancer - then it is tested in those with disease

Generally open label

Absorption, half life, and metabolism are typical data reported

Question 31

Phase II in clinical trials

Answer 31

Larger group of patients with target disease to determine efficacy (100-200 pts)

Typically single-blind

Include inert placebo (positive control), and active investigational agent

Drug failure typically occurs during this phase d/t toxicity or not being efficaceous

Question 32

Phase III in clinical trials

Answer 32

Further establishes drug safety and efficacy in large group of patients (300-3000+) with target disease

Crossover and double-blind design often used

Gather info on overall risk:benefit ratio

Most expensive phase of trial

Question 33

Phase IV in clinical trials

Answer 33

Only after approval to market

Postmarketing study to monitor safety of new drug under actual conditions of use in large numbers of pts

Essential in drugs with SEs that occur in 1/10,000 pts

Ex: COX-2 inhibitors