Drug metabolism reactions Flashcards
Xenobiotic =
foreign compound
Elimination is irreversible removal or loss of a drug from the body. Two mechanisms:
Metabolism and excretion
Describe metabolism
- Major sites are liver and intestine
- Is still a dominant mechanism of drug elimination (may be coupled with transporters)
- Involves enzymatic conversion of a drug to metabolites.
- Metabolites are more polar and hydrophilic than the parent drug and are renally excreted. Prevents drug accumulation
- Properties of molecule are changed.
Describe elimination:
- Elimination of unchanged drug (no metabolic conversion) or its metabolites from the body
- Occurs mostly in the kidney (urinary excretion)
- Occurs also at other sites
- -> Liver (biliary excretion - bile)
- -> Lungs (pulmonary)
Importance of drug metabolism
- Metabolites are generally pharmacologically inactive and less toxic than the parent
Exceptions: - Pharmacologically active metabolites
- Reactive metabolites
- Prodrug – inactive or weakly active drug that produces active metabolite (e.g. Levodopa – Dopamine)
Most common cause of DDI?
Inhibition of metabolic enzymes in the liver/intestine is the most common cause of DRUG-DRUG INTERACTIONS*
- Safety issues and withdrawal of drugs from the market due to severe DDIs
Drug metabolising enzymes factors:
- Show very broad substrate specificity (not just drugs)
- Drugs - variety of chemical structures
- Environmental chemicals
- Dietary chemicals - naturally occurring (phytochemicals) and synthetic
- Endogenous compounds e.g. testosterone, bile acids
- Localisation – predominantly liver, but also intestine and kidney
- Ubiquitous enzymes - present in all animal species
- Original purpose to protect against phytochemicals in diet
- Modern role similar, but exposure more extensive via a wide range of therapeutically used drugs
Comparison of physicochemical properties of parent drugs and metabolites
Parent drug - high lipophilicty , low water solubility, pKa >5, pKa <9, low renal clearance, have therapeutic value, no toxicity
Metabolite - low lipophilicty, high water solubility, strong acid, high clearance, non toxic, no therapeutic value
Role of liver in drug metabolism and elimination
- Most important due to size, blood flow and high enzyme concentration in hepatocytes
- Phase I (cytochrome P450s) and phase II enzymes (e.g., UGT – glucuronidation)
- Some drugs eliminated unchanged via biliary excretion
- Anatomical position of liver - extensive first-pass metabolism
- Infrastructure and subcellular localisation of enzymes (endoplasmic reticulum/microsomes)
Liver- subcellular fractions used for studying drug metabolism in vitro. How?
Endoplasmic reticulum – broken up by homogenisation
- Centrifuged sequentially (differential centrifugation) to give microsomes
- Most oxidation enzymes (Cytochrome P450) are membrane bound and located in microsomes
- Microsomes from human liver, intestine and kidney widely used in drug development
- -> recombinant enzymes, hepatocytes, liver chip also used
- Homogenate of liver tissue –> centrifuged –> breakdown of endoplasmic reticulum produces microsomes –> isolate the microsomes
Drug metabolism reactions:
- Oxidation
- Reduction
- Hydrolysis
- Conjugation
(1-3 = phase 1)
(4 phase 2)
Functional groups
- OH, -COOH, -NH2
- Oxidation is the most important
- Catalysed by a super-family of enzymes - Cytochrome P450s*
Phase 1 reactions:
- Introduce or expose functional groups to change the structure of the molecule
- Oxidation - at C, N or S atoms
- C hydroxylations: aromatic or aliphatic Cs
- Cleavage: loss of alkyl or amino group (N-, O-, S-dealkylation)
- N and S oxidations
- Reduction - acts on nitro and keto groups
- Hydrolysis - acts on ester and amide groups
Examples of phase I metabolic reactions. Hydroxylation - aromatic oxidation:
Aromatic oxidation – results in the formation of phenols
Name the three different types of oxidation reactions:
3 different types of oxidation reactions – aromatic, aliphatic and de-alkylation
Examples of phase I metabolic reactions.
Aliphatic oxidation:
Results in the formation of alcohols
a) Benzylic position – tolbutamide
b) Side chain – ( -1) position - pentobarbitone
