Lecture 5: Intro to Biotransformation, Pharmacogenomics, and Clinical Trials Flashcards Preview

SBL (Skin, Blood, Lymph) Exam 1 and 2 > Lecture 5: Intro to Biotransformation, Pharmacogenomics, and Clinical Trials > Flashcards

Flashcards in Lecture 5: Intro to Biotransformation, Pharmacogenomics, and Clinical Trials Deck (35)
Loading flashcards...

What is Biotransformation?

chemical modification of lipophilic, unionized, or large compounds to terminate their actions and facilitate elimination

- polar, small molecular volume xenobiotics eliminated through renal excretion


What is a Prodrug?

an inactive drug that undergoes biotransformation to become an active drug

- may have a protective functional group that gets removed, allowing the drug to become active


Besides the liver, what are 4 other locations in the body that have considerable biotransforming activity?

GI tract, lungs, skin, and kidneys

- express smaller quantities of the the enzymes required than the liver


What is the First-Pass Effect?

- oral drugs are absorbed in the small intestine and transported to the liver via hepatic portal system for metabolism

- parenteral routes do not undergo first-pass biotransformation


What happens to estrogen and morphine when undergoing First-Pass metabolism?

- GI flora increases the bioavailability of estrogen by increasing enterohepatic cycling

- only 25% of oral morphine doses are bioavailable, making parenteral administration much more desirable


What happens during Phase I of biotransformation? (What does it do, what causes it, and where?)

- catabolic rxn that unmasks a functional group on the drug (oxidation, reduction, hydrolysis)

- rxns carried out by mixed function oxidases (MFOs)

- rxns occur in lipophilic ER membranes in liver


What happens during Phase II of biotransformation? (What does it do, what causes it, and where?)

- anabolic rxns that form a conjugate of the phase I product (polar w/high molecular weight)

- dependent on glucuronic, sulfuric, acetic, and amino acids

- takes place in the liver and is a faster than Phase I rxns


What is the most abundant cytochrome P450 enzyme?


- involved in metabolism of 50% of clinically used drugs

- uses oxygen and hydrogen from NADPH to carry out oxidation of substrates


What are the 4 other major cytochrome P450 enzymes?



What is Succinylcholine and what enzyme is used to metabolize it?

- depolarizing neuromuscular blocking drug

- genetic defect in pseudocholinesterase = metabolize at 50% the normal rate


What is the Slow Acetylator phenotype and who does it most commonly affect?

- autosomal recessive = dec. N-acetyltransferase lvls

- isoniazid, hyralazine, caffeine, other amines metabolized at slower rates = hepatotoxicity

- 50% of US and 83% of French populations


What are 5 common P450 inducers? (PEBRP)

phenytoin, ethanol (chronic), benzo[a]pyrene, rifampin, phenobarbitol


What is the effect of Grapefruit juice on P450?

- irreversibly inhibits CYP3A4 and alters the bioavailability of drugs taken orally


What is the effect of allopurinol and mercaptopurine on xanthine oxidase?

- allopurinol treats excess uric acid and inhibits xanthine oxidase

- xanthine oxidase metabolizes mercaptopurine (cancer treatment drug), so coadministration with allopurinol increases toxic effects


How can acetaminophen become hepatotoxic?

- normally 95% undergoes glucuronidation while 5% is biotransformed by P450s

- when excess intake occurs, hepatic GSH is depleted faster than can be regenerated, so more toxic metabolites accumulate = hepatotoxicity


Genetic variation of CYP2D6 and Codeine/Morphine

- codeine (prodrug) is converted to active morphine, which binds to mu-receptors in CNS and is used to manage mild-moderately severe pain

- people with polymorphisms in CYP2D6 may experience insufficient pain relief OR side effects (drowsiness and respiratory depression)


Genetic variation of CYP2C19 and Clopidogrel

- clopidogrel is acidic antiplatelet prodrug that is converted to active thiol metabolite (only 15% of dose) that causes antiplatelet activity

- people with polymorphisms in CYP2C19 (reduced function) are at an inc. risk for adverse cardiovascular effects (acute coronary syndrome)


Genetic variation of UGT1A1 and Irinotecan

- irinotecan is a topoisomerase I inhibitor prodrug (first line chemotherapy for colon/rectum carcioma)

- metabolized to SN-38 metabolite (TOXIC)

- UGT1A1*6 and UGT1A1*28 polymorphisms are at inc. risk of neutropenia and diarrhea due to SN-38 buildup


Genetic variation of Thiopurine S-Methyltransferase (TPMT) and azathioprine, 6-mercaptopurine (6-MP), and 6-thioguanine (6-TG)

`- normal enzyme attaches methyl group to aromatic/heterocyclic sulfhydrl compounds (deactivates)

- 6-MP/6-TG are activated by HGRPTase to form TGNs (thioguanine nucleotides) that are anticancer agents and have bone marrow toxicity

- TPMT and xanthine oxidase normally inactivate 6-MP and 6-TG, but polymorphisms can lead to a buildup of toxic products


Genetic variation of G6PD and Rasburicase

- G6PD exclusive source of NADPH and glutathione in RBCs

- Rasburicase manages high uric acid lvls in cancer pts on chemotherapy; converts uric acid to allantoin

- hydrogen peroxide is a biproduct that can be reduced by glutathione, so use is NOT permitted in pts. with a G6PD deficiency (African/Mediterranean)


Genetic variation of OATP1B1 and simvastatins

- transporter responsible for uptake of weak acid drugs (statins) and bilirubin

- polymorphism rs4149056 in SLCO1B1 genes can cause low lvls of OATP1B1

- individuals with low lvls are at increased risk of toxicity to skeletal muscle if taking simvastatins to reduce serum lipids (prevent cardiac events)


CYP2C9 alleles and S-warfarin

- CYP2C9*2 and CYP2C9*3 are alleles that lead to reduced metabolism of S-warfarin and are more common in European populations

- CYP2C9*5/*6/*8/*11 alleles are more prevalent in African populations


VKORC1 allele and warfarin

- target of anticoagulant warfarin and a key enzyme in vitamin K recycling process

- the most important polymorphism leads to inc. sensitivity to warfarin and occurs most frequently in Asians and least frequently in Africans (VKORC1-1639G>A polymorphism)


What is a Lead Compound?

- chemical compound that has pharmacological/biological activity and a structure thats used as a starting point for chemical modifications to improve potency, selectivity, pharmacokinetic parameters


What is a Leading Candidate?

- lead compound that has undergone modification after animal and cell screenings

- will undergo preclinical and toxicity testing before human evaluation begins


Why is preclinical testing preformed?

to evaluate a leading compounds safety and toxicity

- identifies human toxicities, designs tests to further study toxic mechanisms, and predicts the most relevant ones to be monitored in clinical trials

- want to test compound in a cellular system that best represents the disease state it will be used on


What is the No-Effect dose, the Minimum Lethal dose (LDmin), and the Median Lethal dose (LD50)?

NE = max dose at which toxic effect is NOT seen
- lower than threshold of harmful effect

Min Leth = smallest dose that kills an animal

Med Leth = does that kills 50% of the animals


What is Phase 0 of clinical testing?

- "microdosing" or subpharmaceutical doses given to human volunteers

- can offer supportive/alternative data that allows selection of suitable drug candidates when animal and in vitro testing isn't reliable

- financially advantageous


What is Phase I of clinical testing?

- determines if humans and animals show different responses to investigational drug and determine limits of safe dosage range

- 25-50 healthy volunteers, though in cases of significant toxicity, subjects with disease state may be included (AIDS/chemo)

- performed in inpatient clinic


What data is reported from Phase I testing? (H/A/M)

absorption, half-life, and metabolism