Lecture 9: biotransformation Flashcards
Drug Biotransformation
•The enzymatically-driven process whereby a substance is changed from
one chemical to another
what is the general strategy for eliminating compounds:
biotransformation into
more polar, and sometimes larger, derivatives
Consequences of biotransformation
1) inactivation (aspirin)
2) active compound to active compound (diazepam->oxazepam)
3) activation (L-dopa)(prodrug)
where does biotransformation mostly occur?
Mostly occurs in the liver at some point between absorption into the general
circulation and renal elimination
First-pass effect
•The first-pass effect is the process by which oral drugs undergo extensive
biotransformation after absorption prior to entering circulation
what drugs do not undergo first-pass biotransformation?
Drugs administered parenterally
phase 1 rxns
- Oxidation, reduction, and hydrolysis
- catabolic
- products more reactive, sometimes more toxic
phase II rxns
-of enzymes that form a conjugate of the substrate
-Conjugation with endogenous substrates such (e.g., glucuronic acid, sulfuric
acid, acetic acid, or an amino acid) to improve water solubility and increase molecular weight
-anabolic
what are phase 1 rxns carried out by?
mixed function oxidases (MFOs) or monooxegenases • Cytochrome P450s (P450 or CYP) • Flavin-containing monooxygenases (FMO) • Epoxide hydrolases (mEH, sEH)
where are enzymes for phase I rxns located?
lipophilic ER membranes of the liver (and
other tissues)
•Phase II enzymes
- UGT – UDP-glucuronosyltransferase
- GST – glutathione-S-transferase
- NAT – N-acetyltransferase
- TPMT – thiopurine methyltransferase
- SULT - sulfotransferase
what are genetic factors in biotransformation
- Polymorphisms in xenobiotic-metabolizing enzymes
* Pharmacogenetic differences in enzyme expression levels
nongenetic factors in biotransformation
- Drug-drug interactions
- Age and sex
- Circadian rhythm
- Body temperature
- Liver size and function
- Nutritional and environmental factors
what are some compounds that are enzyme inducers
phenobarbital, chronic ethanol, aromatic
hydrocarbons such as benzo[a]pyrene (tobacco smoke), rifampin, St. John’s wort
what are compounds that are enzyme inhibitors?
grapefruit juice
• Pharmacogenetics
the study of differences in drug response due to allelic
variation in genes affecting drug metabolism, efficacy, and toxicity at the genomic
level
• Pharmacogenomics
the study of the entire genome to assess multigenetic
determinants of drug response
• Polymorphism
a variation in the DNA sequence that is present at an allele
frequency of 1% or greater in a population
what does acetaminophen overdosed cause hepatotoxicity?
- overwhelms conjugation pathways
- glutathione depleted faster than regenerated
- toxic metabolites accumulate
what is the most common disease producing enzyme defect?
glucose 6-phosphate dehydrogenase deficiency
- causes decrease in NADPH and glutathione
- oxidative stress leads to hemolytic anemia
a mutation in what receptor can lead to malignant hyperthermia?
ryanodine receptor
-increase in Ca2+ at SR-> muscle contraction
what is an ex of a drug that has Variations at multiple gene loci (polygenic effects)?
- Warfarin (Coumadin)
- Polymorphisms in biotransforming enzymes
- Polymorphisms in drug target
lead compound
Defined as a chemical compound that has pharmacological or biological activity and
whose chemical structure is used as a starting point for chemical modifications in order to
improve potency, selectivity, or pharmacokinetic parameters
Investigational new drug (IND)
is the means by which investigators technically obtain
permission from the FDA to proceed with drug distribution
Phase I
- typically first stage in human testing
- 20-100 subjects
- is drug safe? pharmacokinetics?
phase II
- 100-200 patients
- does drug work in patients?
- typically single blind
phase III
1000-6000 patients
- does drug work
- double blind study
- includes patients with target disease
how long does it usually take for a new drug application?
8-9 yrs
what is phase 4?
postmarketing surveillance
No-effect dose:
the maximum dose at which a specified toxic effect is not seen
Minimum lethal dose (LDmin):
the smallest dose that is observed to kill any experimental
animal under a defined set of conditions
Median lethal dose (LD50):
the dose that kills approximately 50% of the animals
IRB
The purpose of IRB review is to assure that appropriate steps are taken to protect
the rights, safety, and welfare of humans participating as subjects in the research
what is the enzyme target of warfarin?
vitamin K epoxide reductase (VCORC1)
what drugs given when patient has G6PD deficiency are more likely to become ROS?
- sulfur group drugs
- fava beans
- infection
- antimalarial drugs
- asprin
- nitrofuantoin
- NSAIDS
- qunidine
- quinine
why can we see hyperbilirubinemia in newborns?
decrease conjugating activity
what does CYP2D6 do
convert codeine to morphine
what does cyp2C19 do?
metabolize acidic drugs
-proton pump inhibitors, antidepressants, antiepileptics, antiplatelet drugs
UGT1A1
- conjugates glucuronic acid onto small lipophilic molecules (bilirubin) so it is more readily excreted
- gilberts syndrome= increase unconjugated bilirubin
thiopurine s-methyltransferase (TPMT
- attaches methyl group on aromatic and heterocyclic sulfhydryl compounds
- pharmacological deactivation of thiopurine drugs
OATP1B1 transporter
- on sinusoidal membrane of hepatocytes
- hepatic uptake of mainly weakly acidic drugs and endogenous compound
BCRP
-efflux transporter in ATP binding cassette superfamily
CYP2C9
drug metabolizing enzyme that acts primarily on acidic drugs (s-warfarin, phenytoin, NSAIDS)
VKORC1
target of warfarin
-can have increase sensitivity to warfarin
