Pharmacogenomics Basics Quiz

Module 4.1: Drug Metabolism (Biotransformation)

• Drug metabolism, also known as biotransformation, involves the conversion of a drug into metabolites.
• The goal of this module is to provide a comprehensive understanding of drug metabolism principles, drug-drug interactions, and genetic impacts on metabolism rates.
• Key terms in drug metabolism include xenobiotic, a foreign substance not used by the body for normal function, with examples like therapeutic drugs, herbal remedies and natural products.

The Fate of a Drug in the Body

• Drug administration involves dissolution (drug dissolving from its form), absorption (primarily in small intestine), distribution (drug circulation throughout body), metabolism (conversion to metabolites), and elimination (removal from body)

General Definition

• Rate of food digestion and energy production
• Conversion of a drug into metabolites.
• Synonymous with drug metabolism.

Importance of Drug Biotransformation

• Structural changes occur inside the body due to metabolism, which can inactivate the drug or produce toxic metabolites.
• Water solubility is improved by metabolism, leading to easier excretion.
• The duration of action of a drug is determined through its rate and extent of biotransformation.

How Drugs are Biotransformed

• Enzymes catalyze various reactions in the body, contributing to drug biotransformation.
• Rate and extent of biotransformation is influenced by several factors, such as drug structure.
• Not all drugs undergo biotransformation.
• Biotransformation isn't always required for drug activation.

Factors Influencing Drug Biotransformation

• Drug structure influences how it's transformed.
• Enzyme affinity for a drug determines if it's a substrate for that enzyme.
• Enzyme levels and metabolic rates vary between individuals.
• Availability of cofactors and co-substrates impact the effect.
• Presence of other xenobiotics, which can act as inhibitors, impacts drug metabolism.

Effects of Biotransformation

• Lipophilic drugs are converted to hydrophilic molecules for easier excretion.
• Active drugs can be transformed into inactive metabolites.
• Active drugs can potentially be converted into other active metabolites.
• Prodrugs are inactive compounds that are metabolized into active metabolites.

Phases of Biotransformation

• Phase 1 reactions involve simple transformations.
  • Examples: oxidation, hydrolysis, reduction, dehalogenation, and dealkylation.
  • Key enzyme involved is cytochrome P450.
• Phase 2 reactions involve conjugation with small molecules.
  • Examples: glucuronidation, sulfonation, acetylation, amino acid conjugation, methylation, and fatty acid conjugation.

Sequence of Reactions

• Primary metabolite is the initial metabolite formed from a drug.
• Secondary metabolite is formed from further metabolism of a primary metabolite
• Phase 1 reactions do not always precede Phase 2 reactions

Substrate Specificity of Biotransformation Enzymes

• Biotransformation enzymes have broad substrate specificity.
• This wide range is an advantage for eliminating a variety of toxins.

Factors Affecting Drug Disposition

• Route of administration influences the drug's journey.
• Interactions with transporter proteins impact drug transit across cell membranes.
• Drug biotransformation chemically modifies a drug in the body.
• The amount of drug administered determines the subsequent effects of that drug.

Sites of Drug Biotransformation

• Liver is the primary site for drug biotransformation.
• Upper intestine involved with orally administered drugs, during absorption.

Systemic Circulation and Presystemic Biotransformation

• Systemic circulation refers to the bloodstream after a drug passes through the liver.
• Presystemic biotransformation is the metabolism of drugs occurring before entering the systemic circulation.
• This is significant when administering orally as a notable portion is metabolized in the gastrointestinal (GI) tract and liver.

Enterohepatic Cycling

• Recirculation of drugs and metabolites between the liver and intestines.
• Drugs are absorbed from the intestines and transported to the liver.
• Metabolized drugs are then transported to the gallbladder.
• Drugs are released back into the intestines, and metabolites are reabsorbed, extending the drug's presence in the body.

Rate of Drugs in the Body

• Majority of drugs are eliminated through metabolism.
• Some amount is excreted through renal and biliary pathways.

Factors Affecting Drug Biotransformation

• Drug structure, enzyme amount, enzyme affinity for drugs, availability of cofactors and co-substrates, presence of other drugs.

Common Functional Groups in Drugs and Their Metabolism

• Drugs contain various functional groups susceptible to enzymatic modification.
  • Examples: amines, cyclohexyl or alkyl chains, aromatic rings, carbonyls or thioketones, alkynes, and alkenes.
  • P450 enzymes are responsible for many conversions related to these functional groups

Drug Design Considerations

• Drug design should consider drug metabolism to avoid unwanted interactions.
• Stabilizing functional groups can prevent enzymatic cleavage.
• Modifying functional groups can reduce drug susceptibility to specific enzymes.
• Example: Replacing a hydrogen atom with a fluorine atom can prevent undesirable reactions with certain drug molecules.

Reduction Reactions

• Drugs with carbonyl, azo, and nitrile groups can undergo reduction reactions by reductases.

Hydrolysis Reactions

• Drugs with ester or amide bonds can be hydrolyzed by esterases within the body.

Glucuronidation

• Involves attaching a glucuronic acid molecule to a drug molecule.
• UDPGA is the glucuronyl co-substrate involved in this process.
• Increases drug water solubility which facilitates excretion.

Sulfation

• Introduces a sulfate group to a drug molecule.
• The co-substrate involved is 3'-phosphoadenosine-5'-phosphosulfate (PAPS).
• Increases drug water solubility.

Glutathione Conjugation

• Attaches a glutathione molecule to a drug molecule.
• GSH (glutathione) is the primary substrate.
• Important for detoxifying reactive metabolites.

Acetylation

• Introduction of an acetyl group to a drug molecule.
• Catalyzed by N-acetyltransferases (NAT).

Amino Acid Conjugation

• Attaches an amino acid to a drug molecule.
• Often involves an activation step followed by reaction with an amino acid.

Methylation

• Introduces a methyl group to a drug molecule.
• Catalyzed by S-adenosylmethionine-methyltransferase (SAM).

Fatty Acid Conjugation

• Attaches a fatty acid molecule to a drug.
• Often increases the lipophilicity of the drug.

Cholesterol Conjugation

• Attaches a cholesterol molecule to a drug molecule.
• Further decreases water solubility.

CYP Enzyme Variability

• Genetic variations among individuals considerably affect the activity of CYP enzymes.
• Enzyme expression levels can vary; some individuals express higher amounts of certain CYP enzymes, impacting drug metabolism.
• Age, gender, diet, and certain drug exposures can influence CYP enzyme expression and activities, potentially modifying drug metabolism.

Factors Affecting Drug Biotransformation

• Enzyme induction or inhibition
• Age and gender
• Circadian rhythms
• Genetic variations.

Drug-Drug Interactions

• Induction or inhibition of enzymes
• Dosage adjustments
• Example involving rifampin and oral contraceptives; charcoal-broiled food and theophylline.

Herbal Remedies

• Certain components in some herbal remedies can induce P450 enzymes, impacting metabolism of other drugs.

P450 Subtypes

• CYP1A2, CYP2E1, CYP2C9, CYP2D6, and CYP3A4
• Different CYP enzymes are important, based on the substrates for these enzymes

Phase III Reactions (Drug Elimination)

• Transporter proteins are crucial in moving drug metabolites across cell membranes
• Lipid-soluble metabolites can cross membranes but water-soluble metabolites require specific transporter proteins