Med School Atlas

    Drug Metabolism

    Pharmacokinetics

    For a more detailed review, see here: Pharmacokinetics

    Absorption requires a drug to be nonpolar and uncharged in order to cross membranes. When drugs are metabolized via first pass, they are processed by intestinal mucosa or the liver before entering plasma. Morphine, especially, has significant first pass effects.

    Drugs can be reabsorbed through entero-hepatic recycling, in which drugs are secreted as biliary into the intestine. This increases the half-life of the drug, even causing a second peak in plasma concentration.

    Drug Metabolism Outcomes

    Four options

    1. Active drug → inactive metabolite
    2. Active drug → active metabolite
    3. Inactive drug → active metabolite
    4. Drug → toxic metabolite

    Nor-meperidine is an example of a drug with a toxic metabolite. It is very dangerous for patients with renal dysfunction or impaired metabolism.

    Locations of Drug Metabolism

    In addition to first pass organs (liver and gut), intracellular metabolism occurs in the smooth ER, mitochondria, cytosol, lysosomes, nuclear envelope, and plasma membrane. The Cytochrome Ps are in the smooth ER.

    Phase 1: Increased reactivity

    Makes the drug more reactive for Phase 2.

    Microsomal oxidation

    Occurs in microsomes (part of smooth ER). The most important microsomal enzyme is Cytochrome P450. Certain substances can induce CYP activity, increasing the metabolism of specific drugs. Inhibitors will do the opposite.

    CYP450 (2D6) mediates the conversion of codeine → morphine.

    There is genetic variability in expression of CYPs.

    • Poor metabolizers are missing metabolic enzymes.
    • Extensive metabolizers have the full complement of metabolic enzymes.
    • Ultra-rapid metabolizers have multiple copies of the metabolic enzymes.

    Nonmicrosomal Oxidation

    Alcohol dehydrogenase
    Alcohol (ethanol, methanol, ethylene glycol) → Acetaldehyde
    Ethanol used to be administered to patients to treat methanol poisoning. Now ethylene glycol is used. Disulfiram inhibits aldehyde dehydrogenase (Acetaldehyde → Acetic Acid). It causes a buildup of acetaldehyde, which produces unpleasant side effects which is useful in treatment of Alcohol Use Disorder.

    Xanthine oxidase
    Hypoxanthine → Xanthine → Uric Acid
    Allopurinol inhibits the formation of uric acid from xanthine. It is used to treat gout.

    Monoamine oxidase
    MAO inhibitors are used as antidepressants because they inhibit the degradation of serotonin in the synaptic cleft. MAOIs can inhibit the breakdown of tyramine from beer, wine, and cheese. This results in hypertension.

    Microsomal reduction

    Facilitated by CYP450

    Hydrolysis

    Facilitated by esterases in the plasma, liver, and other tissues. These are so ubiquitous, drug-drug interactions are not a problem.

    Phase 2: Conjugation reactions

    Substrates are added to the drug to make it more polar and easier to excrete. These occur in the cytosol, with the exception of UDP-glucuronyl transferase which is microsomal.

    Glucuronidation

    Facilitated by UDP-glucuronyl transferase. Processes Chloramphenicol, Morphine, Bilirubin, Irinotecan.

    Important in Chloramphenicol-induced grey baby syndrome. This is an age-related metabolic difference. Babies express UGT less, so they get increased chloramphenicol. This causes respiratory depression and makes them appear grey.

    Acetylation

    Facilitated by Acetyl transferase. Processes Procainamide, Isoniazid, Hydralazine, Amonafide.

    Slow acetylators can get drug-induced lupus with procainamide, hydralazine, and
    isoniazid. Rapid acetylators can get amonafide induced myelotoxicity.

    Glutathione Conjugation

    Facilitated by Glutathione-S-transferases. Processes N-acetyl-para-quinone
    imine (NAPQI), the hepatotoxic metabolite of acetaminophen, into a non-toxic metabolite.

    Alcohol induces CYP2E1 causing a buildup of NAPQI.

    Sulfation

    Facilited by Sulfotransferase. Processes Methyldopa, oral contraceptives, steroid hormones, neurotransmitters.

    Methylation

    Facilited by Methyltransferases (cofactor is S-adenosylmethionine). Processes 6-mercaptopurine (6-MP).

    Drug Transporters

    Important transporters

    • Breast cancer resistance protein (BCRP)
    • Organic anion transporter (OAT)
    • Organic anion transporter 1/3 (OAT1/OAT3)
    • Organic anion transporting polypeptide 1B1/1B3 (OATP1B/OATP1B3)
    • Multidrug and toxin extrusion (MATE) proteins
    • Organic cation transporter 2 (OCT2)
    • P-glycoprotein

    Rosuvastatin is a substrate for OAT and cyclosporine is an inhibitor. This can cause drug-drug interactions and requires a lower dose of rosuvastatin to offset myopathy risk.

    P-glycoprotein is an efflux transporter on the apical membranes in the intestines, liver, kidney, and blood-brain barrier. It pumps substances out of cells to protect the organs.

    Pharmacogenomics

    The study of how a person's genome influences drug behavior. Epigenetics are changes in phenotype but not genotype. There many polymorphisms of metabolic enzymes that can cause altered pharmacodynamics and pharmacokinetics. Just treat the patient as an individual, m'kay?

    If a patient is deficient in a CYP isozyme, they will get similar pharmacokinetic/pharmacodynamic alterations as a patient with a CYP inhibitor.

    Enzymatic examples

    • Thiopurine Smethyltransferase (TPMT): Some people may be unusually sensitive to the myelosuppressive effects of mercaptopurine and develop rapid bone marrow suppression.
    • CYP2D6: Deficit may result in QT prolongation with Thioridazine
    • UGT1A1: UGT1A1*28 homozygotes are at increased risk for neutropenia with Camptosar (irinotecan) treatment
    • CYP2C9/VKORC1: Deficit may lead to over-anticoagulation of warfarin
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