Drug Biotransformation lecture and DSA Flashcards
Pharmacokinetics
looking at dose, concentration, distribution, elimination (metabolized or excreted)
Pharmacodynamics
looking at pharmacologic effect, clinical response (toxicity, effectiveness)
Biotransformation
Enzymatically driven process
Substance changed from one chemical to another by a chemical reaction
Applied to xenobiotics:
- Substances foreign to the body
- Sources: Environmental pollution, Food additives & processed foods, Cosmetics, Drugs
Some eliminated via renal excretion (polar compounds, small molecular volume)
Most are lipophilic and require modification to be efficiently eliminated
Drug biotransformation
Significance: terminates drug action and facilitates elimination
Chemical modification of lipophilic, unionized, or large compounds
Biotransformation can be anabolic as well as catabolic
Biotransformation vs. metabolism:
- We use the term biotransformation instead of “metabolism” because biotransformation reactions often involve synthetic/anabolic reactions as well as “breakdown”/catabolic reactions.
General strategy: Biotransformation into more polar, and sometimes larger, derivatives
Consequences of Biotransformation: 4
- Inactivation: Acetylsalicylic acid (aspirin) --> acetic acid + salicylate
- Active to Active or toxic metabolite
Diazepam –> N-desmethyldiazepam (active metabolite with long half-life) - Activation of prodrug
L-dopa (prodrug) –> dopamine - unexcretable drug converted to an excretable metabolite
Prodrug
an inactive drug that undergoes biotransformation to become an active drug
Sites of Biotransformation
Every tissue has some ability to metabolize drugs
Major site of biotransformation = liver
Most occurs here at some point between absorption and elimination
Other sites = GI tract, lungs, skin, and kidneys
Enzymes may be located subcellularly in the ER, mitochondria, cytosol, lysosomes, nuclear envelope, or plasma membrane
First-Pass Effect
Process by which oral drugs are absorbed in the small intestine and transported to liver via the hepatic portal system Undergo extensive metabolism Greatly limits bioavailability Example: morphine Bioavailability: 17-33%
bioavailability
Amount of drug dose that reaches systemic circulation
Some drugs metabolically inactivated in the stomach:
- Acidity
- Digestive enzymes
- intestinal bacteria
Normal GI flora can increase the bioavailability of certain drugs:
Estrogens used in contraception
GI bacteria increase enterohepatic cycling of metabolites
Antibiotics may reduce estrogen efficacy
Phase I reactions
Catabolic
Enzymes convert parent drug to a more polar metabolite
Introduces or unmasks a functional group (-OH, -NH2, -SH, -COOH, -O)
Most common reactions: oxidation, reduction, and hydrolysis
Products can be more reactive & sometimes more toxic than parent drug
Carried out by mixed function oxidases (MFOs) or monooxegenases Cytochrome P450s (P450 or CYP) Flavin-containing monooxegenases (FMO) Epoxide hydrolases (mEH, sEH)
Phase I enzymes located in lipophilic ER membranes of liver (and other tissues)
Phase II Reactions
Anabolic
Enzymes form a conjugate of the substrate (phase I product)
Conjugation with endogenous substrates (e.g., glucuronic acid, sulfuric acid, acetic acid, or an amino acid) to improve water solubility & increase MW
Enzymes form conjugates of the substrate
- Substrate often the phase I product
Conjugates are polar molecules with:
- Higher molecular weight
- Readily excreted (renal & biliary)
- Often inactive compared to precursors
Conjugation occurs at significantly faster rate than phase I
Ensures efficient elimination & detoxification of most drugs
Endogenous reactants:
- UDP glucuronic acid (UGT enzymes)
- Acetyl-CoA (NAT enzymes)
- Glutathione (GSH) (GST enzymes)
- Glycine
- 3’-Phosphoadenosine-5’-phosphosulfate
- S-adenosyl-methionine
- Water
Cytochrome P450 Enzymes
Superfamily of enzymes
Named: CYP3A4
CYP(Root) 3(Family) A(Subfamily) 4(Gene #)
Over 50 identified
CYP1A2, CYP2C9, CYP2D6, CYP2E1, CYP3A4
Contain molecule of heme non-covalently bound to the polypeptide chain
Metabolize many structurally diverse chemicals
Common Phase II reactions
glucoronidation, sulfation, acetylation, methylation, glutathione conjugation
Drug Biotransformation: Clinical Relevance?
Individual differences in drug distribution & rates of drug metabolism/elimination
Differences due to:
Genetic factors – Polymorphisms in xenobiotic metabolizing enzymes, Pharmacogenetic differences in enzyme expression
Non-genetic factors –
- Drug-drug interactions
- Age & sex
- Circadian rhythm
- Body temperature
- Liver size & function
- Nutrition
- Environment
Genetic differences: succinylcholine
Depolarizing skeletal muscle relaxant
Those with genetic defects may metabolize at 50% of the rate
can -> respiratory paralysis
Succinylcholine? Think: “sucking air”
Genetic differences: Slow acetylators
Autosomal recessive trait
Decrease in N-acetyltransferase levels
Isoniazid (TB), hydralazine (hypertension), and caffeine
Occurs ~50% of US population, more frequently in Europeans, less commonly in Asian populations
drug-drug interactions (DDIs)
Drug biotransformation –> inactivates drug & facilitates elimination
Extent of elimination determines efficacy & toxicity
DDIs are a leading cause of adverse drug reactions (ADRs)
Determine identity of CYPs which metabolize specific drugs
CYP specific DDIs
- Enzyme induction
- —-Increased rate of enzyme synthesis
- —-Reduced rate of enzyme degradation
- Enzyme inhibition
- —- Reversible (competitive or non-competitive)
- —- Irreversible (suicide inhibition)
P450 Enzyme Induction
Some P450 substrates can induce P450 activity
Induction leads to increased substrate metabolism
– Generally results in decreased pharmacologic action
P450 induction may exacerbate metabolite-mediated toxicity in cases where biotransformation results in toxicity
Inducers:
- Phenobarbital
- Chronic ethanol
- Aromatic hydrocarbons
- Rifampin
- Anticonvulsants
P450 Enzyme Inhibition (2 types)
Competitive inhibition (reversible)
- Direct binding to the heme iron and reducing metabolism of substrates
- Example: macrolide antibiotics (erythromycin)
Suicide inhibition (irreversible)
- Covalent interaction of metabolically generated reactive intermediate that reacts with the P450 apoprotein or heme moiety
- Example: chloramphenicol, metabolized via CYP2B1
Grapefruit juice effect
- Grapefruit juice + oral drugs can irreversibly inhibit intestinal CYP3A4
- Inhibition alters bioavailability of many drug classes
- —- Antihypertensives, immunosuppresants, antidepressants, statins
Biotransformation: Fetus, Newborn, Elderly
Hepatic enzyme activity low in the neonate, increases rapidly in postnatal period, heterogeneous in elderly
Premature infants have decreased conjugating activity
- Neonatal jaundice (hyperbilirubinemia)
- Increased toxicity from drugs such as chloramphenicol and opioids
Fetus and neonate highly susceptible to drug toxicity
- Poorly developed blood-brain barrier
- Weak enzyme activity
- Immature excretion mechanisms
Drug metabolism may decrease with age
- Most important factor: liver and kidney disease
Disease States and Biotransformation
Acute and chronic diseases (may affect organ architecture or function)
- Alcoholic hepatitis or cirrhosis
- Acute viral or drug-induced hepatitis
- Biliary cirrhosis
- Hemochromatosis
- Chronic, active hepatitis
Cardiac disease may impair elimination of drugs with flow-limited metabolism
- Propranolol, isoniazid, lidocaine, morphine, verapamil
Metabolism to Toxic Products
Phase I reactions transform drugs to intermediates which phase II enzymes quickly convert to products which can be safely eliminated
Several compounds have been shown to be transformed to toxic intermediates
- Toxic metabolites will not accumulate if biotransformation keeps pace
- When cosubstrates limited, toxic pathways may prevail
Examples:
- Acetaminophen
- Non-steroidal anti-inflammatory drugs (NSAIDs)
- Isoniazid
Toxic products of acetominophen
Normal adult dose of 1.2 g/day
95% undergoes glucuronidation & sulfation
5% via P450 pathways
When intake > therapeutic doses
- Glucuronidation & sulfation pathways saturated
- Alternate pathway is used
- Hepatic GSH depleted faster than regenerated
- Accumulation of toxic metabolites
- Hepatotoxicity
Premature infants and conjugating activity
i) Hyperbilirubinemia in the newborn:
(1) During the metabolism of fetal hemoglobin (increased red blood cell breakdown/turnover), bilirubin levels accumulate in the blood.
(2) Due to the immature hepatic metabolic pathways, newborns are unable to conjugate bilirubin with UDP glucuronic acid (UDP glucuronosyltransferase levels are low) and bilirubin is unable to be excreted.
(3) Bilirubin-induced encephalopathy is a concern when levels become dangerously high.
