Introduction to Biotransformation, Pharmacogenomics, and Clinical Drug Trials Lecture (Dr. Kruse) Flashcards
Drug Biotransformation
- The enzymatically‐driven process whereby a substance is CHANGED from one chemical to another
- Biotransformation reactions can be ANABOLIC as well as CATABOLIC (biotransformation vs. metabolism)
- The general Strategy for ELIMINATING compounds: biotransformation into more POLAR, and sometimes LARGER, derivatives
- POLAR and WATER SOLUBLE products are more readily EXCRETED by the KIDNEYS
- Most METABOLIC PRODUCTS are LESS Pharmacodynamically ACTIVE than the Parent Drug
Consequences of Biotransformation
1) INACTIVATION Acetylsalicylic acid (aspirin) → ace c acid + salicylate
2) ACTIVE COMPOING → active compound Diazepam → Oxazepam
3) ACTIVATION
- L‐dopa → dopamine
a) PRODRUG: an INACTIVE drug that undergoes biotransformation to BECOME an ACTIVE drug
** Mostly occurs in the LIVER at some point BETWEEN Absorption into the General Circulation and RENAL Elimination
First Pass Effect
- All XENOBIOTICS absorbed from the Small Intestine are TRANSPORTED to the LIVER via the Portal system
- The FIRST-PASS EFFECT is the process by which ORAL DRUGS undergo extensive Biotransformation after absorption prior to entering circulation
- Drugs administered Parenterally DO NOT UNDERGO FIRST-PASS BIOTRANSFORMATION
- The FIRST-PASS EFFECT greatly LIMITS the BIOAVAILABILITY of some drugs such that alternative routes of administration must be explored
a) Example: MORPHINE
b) ORAL BIOAVAILABILITY is roughly 25%
c) PARENTERAL Administration is preferred
The Phases of Biotransformation
As a general rule:
1) PHASE I reactions result in the BIOLOGICAL INACTIVATION of the DRUG
2) PHASE II reactions produce a metabolite with improved WATER SOLUBILITY and INCREASED Molecular Weight (enhances elimination)
The Phases of Drug Metabolism
1) PHASE I reactions consist of enzymes that convert the parent drug to a MORE POLAR METABOLITE by introducing or unmasking a functional group (‐OH, ‐NH2, ‐SH, ‐COOH, ‐O)
a) Oxidation, Reduction, and Hydrolysis reactions are most common
b) Phase I reactions are CATABOLIC!!!!!
c) Phase I products can be more Reactive and sometimes MORE TOXIC than the parent drug
2) PHASE II reactions consist of enzymes that form a CONJUGATE of the substrate (phase I product)
a) Conjugation with endogenous substrates such (e.g., GLUCURONIC ACID, SULFURIC ACID, ACETIC ACID, or AMINO ACID) to Improve WATER SOLUBILITY and Increase molecular weight
b) Phase II reactions are ANABOLIC!!!!!!!
3) Typical ORDER is Phase I followed by Phase II reactions (but not always – isoniazid)
Phase I Reactions
- Oxidations, Reductions, and Hydrolysis reactions
- Products are generally more reactive and may be more TOXIC than parent drug
•Phase I reactions are carried out by Mixed Function Oxidases (MFOs) or monooxegenases
a) CYTOCHROME P450s (P450 or CYP)
b) FLAVIN-CONTAINING MONOOXYGENASES (FMO)
c) EPOXIDE HYDROLASES (mEH, sEH)
•Phase I enzymes are LOCATED in LIPOPHILIC ER membranes of the LIVER (and other tissues)
Key Enzymes in Biotransformation
1) CYTOCHROME P450 (CYP450) – PHASE I !!!!!!!!!!!
a) Superfamily of enzymes that carry out phase I reactions
b) Of the more than 50 P450s identified in humans, the most important are CYP1A2, CYP2A6, CYP2D6, CYP2E1, and CYP3A4*!!!!!!!!!!!!!!!
2) PHASE II ENZYMES
a) UGT – UDP Glucuronosyltransferase
b) GST – Glutathione‐S‐Transferase
c) NAT – N‐Acetyltransferase
d) TPMT – Thiopurine Methyltransferase
e) SULT ‐ Sulfotransferase
Clinical Relevance of Biotransformation
- Individuals differ in drug distribution and in their rates of drug metabolism and elimination
- Differences in individual biotransformation rates and efficiency are some of the many factors that may affect drug dose and frequency of administration among individuals
• GENETIC FACTORS:
a) POLYMORPHISMS in Xenobiotic‐metabolizing ENZYMES
b) PHARMACOGENETIC differences in ENZYME EXPRESSION levels
• NON-GENETIC FACTORS:
- Drug‐drug interactions
- Age and sex
- Circadian rhythm
- Body temperature
- Liver size and function
- Nutritional and Environmental factors
Examples of Genetic Differences that affect Biotransformation
1) Succinylcholine (Pseudocholinesterase Degrades it)
2) Slow acetylator phenotype for N‐acetyltransferase enzyme
Examples of Non-Genetic Differences (Drug-Drug Interactions, DDIs)
1) ENZYME INDUCTION:
• Well characterized Inducers: PHENOBARBITAL, CHRONIC ETHANOL, AROMATIC HYDROCARBONS such
as [a]pyrene (Tobacco Smoke), RIFAMPIN, St. John’s WORT
2) ENZYME INHIBITION:
• Reversible and Irreversible Inhibition
• GRAPEFRUIT JUICE EFFECT!!!!!!!!!
3) Biotransformation as we age • Hepatic blood flow?!!!!
4) Disease STATES and Biotransformation
• Liver disease, Cardiac disease
Metabolism to Toxic Products
1) Acetaminophen‐induced HEPATOTOXICITY
- For an adult dose of 1.2 g/d:
a) 95% Glucuronidation and Sulfation
b) 5% P450‐dependent GSH conjugation!!!!! - When ACETAMINOPHEN intake exceeds therapeutic doses:
a) Glucuronidation and Sulfation pathways are SATURATED and P450 pathways becomes INCREASINGLY IMPORTANT
b) Over time, HEPATIC GSH is DEPLETED FASTER than is regenerated
c) TOXIC metabolites ACCUMULATE resulting in hepatotoxicity!!!!
2) What about Alcohol consumption and Acetaminophen?
• See table 4‐2 in Katzung (p. 62)
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
Drug Response Variability is Genetically Determined (in part)
VARIATIONS OCCUR IN:
• PHARMACOKINETICS – variation in the rate at which the body Absorbs, Transports, Metabolized, or
Excretes a drug/metabolites
• PHARMACODYNAMICS – allelic variation in a drug’s downstream targets, such as Receptors, Enzymes,
or Metabolic pathways
