Biotransformation Flashcards
Importance of biotransformation
The processing of xenobiotics for elimination- xenobiotics are foreign compounds including environmental chemicals, food toxins, therapeutic drugs, and recreational drugs
Hydrophilic drugs
Polar, ionize in physiological pH, easily excreted, low therapeutic effectiveness, short half-life
Lipophilic drugs
Most drugs, can cross membranes to get to site of action, difficult to eliminate, must be processed to prevent toxicity
Functions of biotransformation
Metabolize, detoxify, and render drug less toxic (metabolism)
Eliminate the drug from the body (disposition)
Phases of biotransformation
Phase I- metabolism and detoxification
Phase II- elimination, makes drug more excretable
Most important cytochrome P450 families
CYP1, CYP2, CYP3, CYP4
Important CYP enzymes
CYP3A4- responsible for >50% of prescription drug metabolism, CYP2D6, CYP2C, CYP1A2, CYP2E1
Induction
Transcriptional activation of the enzyme
Tobacco smoke, charcoal broiled meat
Induces CYP1A
Barbiturates (anxiolytics)
Induces CYP2B1
Ethanol
Induces CYP2E1
Steroids
Induces CYP3A4
Fibrates (LDL lowering drugs)
Induces CYP4A
Cimetidine (gastric ulcer medication)
Inhibitor, binds tightly to heme and reduces metabolism of endogenous substrates
Ketoconazole (anti-fungal medication)
Inhibitor, binds tightly to heme and reduces metabolism of endogenous substrates
Macrolides (antibacterial)
Inhibitor, metabolized to reactive species, complex with heme iron and rend it catalytically inactive
Suicide inhibitors
Irreversibly inhibit CYP via covalent binding to the heme or protein portion of the enzyme
Phase I
Enzymes add polar group onto the drug to make it more polar (hydrophilic), allowing it to be conjugated, includes: oxidation, reduction, and hydrolysis reactions
Phase I enzymes
Most are heme protein mono-oxygenases of cytochrome P450 gene family
Phase II
Drugs that have undergone phase I may have chemical groups that allow them to conjugate with endogenous substances, conjugates are polar, often inactive, and readily excreted
Consequences of conjugation reactions
May lead to formation of reactive species responsible for drug toxicity
Acetaminophen processing
95% goes through conjugation- glucuronidation, sulfation
5% goes through P450 metabolism- makes reactive agent NAPQI, GSH conjugates NAPQI for excretion
Acetaminophen overdose
Conjugation reaction is saturated, more goes through P450 and saturates GSH conjugation, NAPQI accumulates, forms protein adducts in liver, hepatic necrosis, death
Alcoholics and acetaminophen OD
More susceptible because ethanol induces the same P450 and shifts reaction of the drug to P450 metabolism
Treating acetaminophen OD
Give N-acetylcysteine (NAC), provides SH group to bind toxic protein, creates cysteine conjugate for excretion, must give NAC within 8-16 hours
2D6 polymorphism, PM phenotype
Associated with breast cancer relapse in those treated with tamoxifen, dependent on 2D6 metabolism
2D6 polymorphism, UM phenotype
Displays in 1/3 of Ethiopians and Saudi Arabians, patients require 2-3x dose of nortriptyline (antidepressant), poor response correlates with higher suicide rates, prodrug codeine is metabolized faster to morphine, faster sedation
2C19 polymorphism, PM phenotype
Poor metabolizer, occurs in 3-5% of Caucasians, 18-23% of Japanese, lack hydroxylation activity and S- and R-forms of mephenytoin accumulate, cause sedation and ataxia
2C19 polymorphism, EM phenotype
Extensive metabolizer, S-form is hydroxylated by 2C19, conjugated by glucuronidation, excreted into urine, R-form is slowly demethylated into active nirvanol
2C9 polymorphism
Impaired formation or inactive protein, occurs in 6-13% of Caucasians, increases patient sensitivity to warfarin, can lead to excessive bleeding and death
Warfarin
Inhibits vitamin K epoxide reductase- required for recycling vitamin K which is crucial in activation of clotting factors, warfarin inhibits clotting
Slow acetylators
Occur in 50% of Whites and Blacks, associated with higher incidence of isoniazid-induced peripheral neuritis, autoimmune disorders, bladder cancer
Newborn child biotransformation
Capable of carrying out many, but not all biotransformation reactions
Gray baby syndrome
Chloramphenicol (antibacterial) excretion requires oxidative transformation followed by conjugation, oxidative metabolite is toxic, can accumulate if not conjugated (newborns)
Elderly biotransformation
Reduced metabolic capacity due to decline in liver mass, hepatic blood flow, reduced renal function, some take multiple medications that can contribute to drug-drug interactions
Androgenic hormone levels
Associated with sex-dependent differences in drug metabolism
Diet and environment
May alter biotransformation by inducing or inhibiting P450 enzymes
Grapefruit juice
Inhibits CYP3A4
St. John’s wart
Herbal medication for mood stabilization, induces CYP3A4
Polycyclic aromatic hydrocarbons in cigarette smoke
Induces CYP1A1, CYP1A2, CYP2E1
Lead
Induces heme-oxygenase enzyme, breaks down P450
Drug-drug interactions, two drugs metabolized by the same enzyme
The drug with lower affinity accumulates and becomes toxic
Drug-drug interactions, one drug induces the enzyme
Can increase or decrease the efficacy of the other drug
Drug-drug interactions, one drug inhibits the enzyme
Reduces the metabolism of the other drug
Rifampin (antibacterial) drug-drug interaction
Induces CYP3A4, increases the metabolism of estrogenic component of estrogen-based contraception
Erythromycin (macrolide antibiotic) drug-drug interaction
Metabolized by CYP3A4, metabolite complexes with 3A4 and inhibits the enzyme, inhibits 3A4 metabolism of other drugs
Methanol intoxication drug-drug interaction
Intoxication results in blindness/death due to toxicity of formaldehyde metabolite, ethanol competes with methanol for oxidation by alcohol dehydrogenase, delayed methanol oxidation reduces metabolite formation, allows time for renal excretion
Liver diseases and biotransformation
Main site of biotransformation, liver diseases (hepatitis, cirrhosis, cancer) will decrease enzymes required for metabolism
Cardiac diseases and biotransformation
Can compromise blood flow, reduce drug delivery to the heart for effect, reduce drug delivery to the liver for metabolism
Thyroid diseases and biotransformation
Thyroid hormone regulates rate of metabolism, hyperthyroidism increases drug metabolism, hypothyroidism decreases drug metabolism
Kidney diseases and biotransformation
Decreases drug excretion
