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A. Major Determinants of Drug Metabolism [2]navigator

  1. Generally divide drug metabolism into two phase (I and II)
    1. Phase I - involve metabolic modification of drug (usually P450 enzymes)
    2. Phase II - synthetic conjugation reactions
  2. Phase I Reactions
    1. Mainly carried out in the liver
    2. Selected P450 enzymes are expressed in the right ventricle of the heart [9]
    3. Oxidation Reactions - Endoplasmic Reticulum (microsomal) and non-ER reactions
    4. Reduction
    5. Hydrolysis
  3. Endoplasmic Reticulum Oxidation Reactions
    1. Aromatic or alphiphatic hydroxylations
    2. Deamination
    3. Dealkylation
    4. S-Oxidation
  4. Reduction Reactions (ER)
    1. NADP- cytochrome c reductase
    2. Reduced NAD-cytochrome b5 reductase
  5. Non-ER Oxidation Reactions
    1. Alcohol Dehydrogenase - cytosolic; ethanol, chloral, vitamin A, retinine
    2. Diamine Oxidase - mitochondrial membrane bound
    3. Monoamine Oxidase - mitochondrial membrane bound (see below)
  6. Phase II Reactions
    1. Glucuronidation - usually for secretion in bile
    2. Acetylation
    3. Sulfation
    4. Amidation
    5. Glutathione
    6. Amino acid reactions - mainly glycine and glutamine
  7. Drug Transport [11]
    1. Several transporters involved in absorption of drugs from intestinal tract
    2. Also play a role in blood-brain (blood-testis) barrier transport
    3. Major transporter is multidrug resistance gene 1 (mdr1, also called Pgp1) [17]
    4. This is an ATP-dependent pump which transports small molecules out of cells
    5. Mdr1 is involved in digoxin, chemotherapy, antiretroviral therapy, and other drug transport
    6. Mutation in exon 26 of mdr1 codes for a mutant enzyme
    7. Patients homozygous for exon 26 have increased serum levels of digoxin
    8. Verapamil (calcium blocker) and quinidine are inhibitors of mdr1
    9. Digoxin, fexofenadine, cyclosporine, others are excreted by mdr1 [17]
  8. Molecules undergoing ONLY phase I reactions are often reactive and therfore toxic
    1. Reactive oxygen species generally must be detoxified, often through Phase II reactions
    2. Therefore, Phase II reactions are often key to safe catabolism of drugs
    3. Many enzymes involved in cellular stress pathways are involved in drug metabolism
  9. Environmental Determinants of Drug Interactions
    1. Smoking - mainly tobacco
    2. Increased alcohol intake
    3. Drug-Drug interactions
    4. Drug-Herb interactions [8]
    5. Specific foods - particularly grapefruit juice (P450 inhibitor), liquorice
    6. Grapefruit juice in large amounts inhibits intestinal (and less so hepatic) CYP3A4 can reduce clearance of drugs metabolized by CYP3A4 [19]
    7. Grapefruit juice should be avoided with amiodarone, carbamazpeine, cyclosporine, sirolimus and tacrolimus [19]
  10. Pharmacogenetics and Pharmacogenomics [15,16]
    1. Influence of genetic (DNA polymorophisms) and gene expression (RNA, protein) on response to or side effects from pharmacologic agents
    2. Most important overall for polymorphisms in drug metabolizing enzymes, mainly phase I
    3. Some phase II enzymes also have important polymorphisms
    4. Individual genotyping (determining specific DNA sequences) may be increasingly employed to select patients for specific drugs [10,11]
    5. Similarly, DNA polymorphorisms may be assessed to avoid use of specific agents in patients prone to side effects [12]

B. Phase II Conjugation Reactionsnavigator

  1. Glucuronidation
    1. Glucuronyl transferase involved in conjugation reaction
    2. Glucuronic acid is conjugated to carboxyl groups (more commonly) or hydroxyl groups
    3. Key -COOH glucuronidation for bilirubin metabolism, salicylates, lorazepam
    4. Key -OH glucuronidation for morphine, acetaminophen, and chloramphenicol
    5. Mild deficiency of glucuronide formation leads to Gilbert Syndrome
    6. Severe deficiency of glucuronide formation leads to Crigler-Najjar Syndrome
    7. These deficiencies cause excess unconjugated bilirubin
    8. Deficiency of UGT1A1 enzyme associated with increased irinotecan toxicity
  2. Acetylation
    1. Humans are highly polymorphic for rapidity of acetylation
    2. Acetylases are cytosolic enzymes found in many cell types
    3. Utilize acetyl coenzyme A for conjugation reaction
    4. High levels in leukocytes, gastrointestinal cells, liver Kupfer (non-parenchymal) cells
    5. Major targets include isoniazid, hydralazine, procainamide
    6. Polymorphisms in N-acetyltransferase 2 lead to "slow acetylator" phenotype
    7. Slow acetylator patients metabolize certain drugs like isoniazid, hydralazine, procainamide at very slow rates [15]
    8. There are also ultrarapid metabolizers with highly increased levels of this enzyme
  3. Methylation
  4. Sulfation
  5. Addition of Glutathione: Glutathione S-transferase
  6. Catechol O-methyltransferase
    1. ~25% of whites have slow metabolism phenotype
    2. Mainly affects metabolism of levodopa (and some other catecholamines)
  7. Aminoacylation
  8. Thiopruine S-transferase
    1. ~1:300 whites and 1:2500 Asians have slow metabolizer phenotype
    2. Mercaptopurine and azathioprine metaboism is slowed >10 fold
    3. These agents can be quite toxic or fatal in slow metabolizer patients

C. Overview of Key Organs Involved in Drug Metabolismnavigator

  1. Liver
    1. Major site of drug metabolism, particularly Phase I reactions (P450 enzymes)
    2. Of particular importance for compounds entering through gastrointestinal tract
    3. Polymorphisms in P450 enzymes in 2-20% of population can lead to variable drug levels [11]
  2. Gastrointestinal (GI) Tract
    1. Primarily in the ileum
    2. Expression of various P450 enzymes, particularly CYP3A (mainly CYP3A4, some CYP3A5)
  3. Intestinal Bacteria
    1. Important for drugs undergoing enterohepatic circulation
    2. Bacteria may deconjugate (mainly glucuronides) leading to reabosprtion
    3. May also produce various agents (such as vitamin K), which can interact with other drugs
  4. Kidney
    1. Formation of polar metabolites of drugs permits urinary excretion
    2. This may occur by direct filtration or via tubular secretion
  5. Endothelium
    1. Now known that endothelium has multiple metabolic capabilities
    2. Includes active bradykininase (angiotensin converting enzyme)
  6. Body Fat
    1. Major site for deposition of lipophilic compounds
    2. Accumulation of drug and/or metabolites here may lead to highly variable properties
  7. Drug-Drug Interactions
    1. Food, in general, stimulates gastric motility and increases potential absorption
    2. Food stimulates gastric acid secretion, which can alter drug stability and absorption
  8. Other Organ-System Dysfunction
    1. Cardiac suppressants may reduce perfusion to organs and alter drug metabolism
    2. Liver failure can have dramatic effects on drug metabolism
    3. Renal insufficiency can cause accumulation of drug and/or metabolites
  9. First Pass Effects
    1. Generally: metabolism of compound in a specific organ prior to systemic distribution
    2. Typically refers to oral compounds, which are initially metabolized in GI tract and liver
    3. First pass effects may reduce systemic absorption substantially
    4. Inhibitors of first pass metabolism can greatly increase drug absorption
    5. May also refer to inhaled agents (pulmonary metabolism), rectal or nasal delivery

D. Role of Liver in Drug Metabolismnavigator

  1. Primary Conversion Reactions
    1. Mainly related to oxidation through Cytochrome P450 System (endoplasic reticulum)
    2. Name derived from absorption peak of complex of cytochrome with carbon monoxide
    3. Other enzymes can use P450 cytochromes including arachidonate oxidizing enzymes
    4. Alcohol dehydrogenase is another oxidatizing enzyme
  2. Many of these systems are polymorphic in humans
  3. Chronic EtOH induces Cytochrome P450-2E1 and depletes glutathione
  4. Increasing evidence that detoxification of reactive oxygen metabolites is critical to safe metabolic conversion of drugs and other organic molecules

E. Kidney Metabolismnavigator

  1. Renal Enzymes
  2. Glomerular Filtration
  3. Tubular Secretion

F. Lung Metabolismnavigator

  1. Detoxification of vasoactive amines
  2. Angiotensin Converting Enzyme (ACE)
    1. Multiple enzymatic functions including conversion of angiotensinogen to angiotensin I
    2. Very important role in breakdown of brakykinin and substance P
    3. ACE is also present in endothelium

G. Cytochrome P450 Enzymes (CYP): Overview [13,15,17]navigator

  1. Cellular chromophore named for pigement (P)
  2. Pigment has 450nm spectral peak when reduced and bound to carbon monoxide
  3. Humans have 57 CYP genes and 33 pseudogenes; 18 families, 42 subfamilies
    1. Families include enzymes with at least 40% homology (designated by number)
    2. Genes sharing at least 55% identity make up subfamilies (designated by letter)
  4. Most drugs are metabolized by CYP1, 2, 3 and 4
  5. CYP3A subfamily is controlled by transcriptional induction
    1. Molecules activating CYP3 family bind to a ligand activated transcription factor
    2. This factor, pregnane X receptor (PXR) or steroid and xenobiotic receptor
    3. PXR is member of nuclear hormone recpetor superfamily
    4. PXR binds small molecules and activates transcription of CYP3A
    5. Constitutive androstane recpetor (CAR) can activate some CYP3A and CYP2B genes
  6. Most other CYPs are involved in steroid biosynthesis including arachidonate metabolites
  7. Genes in this class of proteins are highly polymorphic (except CYP3A4) and this can lead to differences in drug metabolism across patients
  8. Polymorphisms in CYP 2C9, 2C19, and 2D6 are clinically important [15,16]
    1. Slow metabolizers (typically <5%)
    2. Normal metabolizers (most common)
    3. Ultrarapid metabolizers (typically <5%)
    4. Vary across race and ethnic groups

H. Cytochrome P450 Enzymes: Selected Substrates and Inhibitors [1,3,6,7,17]navigator

  1. P450 1A1/2 (metabolizes ~10% of drugs)
    1. caffeine
    2. theophylline
    3. clozapine
    4. imipramine
    5. R-warfarin
    6. sparteine
    7. Induction: cigarette smoking, omeprazole
    8. Inhibition: fluvoxamine
  2. P450 2A6 (metabolizes ~3% of drugs)
    1. warfarin
    2. nicotine
    3. Induction: barbiturates
    4. Inhibition: 8-methoxypsoralen
  3. P450 2B6 (metabolizes ~3% of drugs)
    1. phenobarbitone
    2. cyclophosphamide, ifosfamide
  4. P450 2C8/9 (metabolizes ~15% of drugs)
    1. ibuprofen, diclofenac, naproxen, piroxicam
    2. torsemide
    3. S-warfarin
    4. tolbutamide
    5. Induction: rifampin
    6. Inhibition: fluoxetine, sulfinpyrazone
    7. Polymorphisms are clinically important
  5. P450 2C19 (metabolizes ~8% of drugs)
    1. omeprazole, lansoprazole
    2. propranolol
    3. diazepam (minor route)
    4. imipramine
    5. pentamidine
    6. phenytoin (dilantin)
    7. Polymorphisms are clinically important
  6. P450 2D6 (metabolizes ~20% of drugs)
    1. captopril
    2. diphenhydramine
    3. ondansetron
    4. ß-blockers: metoprolol, timolol, propranolol, labetalol, alprenolol, carvedilol, bufuralol
    5. anti-arrhythmics: propafenone, flecainide, mexilitine
    6. codeine, oxycodone, hydrocodone
    7. SSRIs and SNRIs: fluoxetine, paroxetine, venlafaxine
    8. tricyclics: amitriptyline, notriptyline, imipramine (part), desipramine, clomipramine (part)
    9. perhenazine, haloperidol
    10. Inhibition: quinidine, paroxetine, fluoxetine
    11. Reduced levels of 2D6 lead to severe side effects of codeine, other agents
    12. Polymorphisms are clinically important
  7. P450 3A4/5 (metabolizes ~35% of drugs) [20]
    1. calcium blockers: felodipine, nifedipine, diltiazem, verapamil
    2. R-warfarin
    3. propafenone, quinidine
    4. cyclosporine, tacrolimus
    5. steroids: dexamethasone, ethinyl estradiol, testosterone
    6. benzodiazepines: alprazolam, clonazepam, diazepam, midazolam, triazolam, zolpidem
    7. nefazodone, sertraline, venlafaxine
    8. tricyclic antidepressants (demethylation)
    9. carbamazepine
    10. atorvastatin, lovastatin
    11. losartan
    12. sildenafil
    13. Induction: carbamazepine, efavirenz, nevirapine, phenytoin, phenobarbital, rifabutin, rifapentine, rifampin, dexamethasone, St. John's Wart
    14. St. Johhn's Wart specifically induces CYP3A4 but not CYP2D6 [18]
    15. Moderate Inhibitors: amprenavir, cirpfloxacin, diltiazem, erythromycin, fluconazole, fluvoxamine, grapefruit juice, norfloxacin, verapamil
    16. Potent Inhibitors: amiodarone, ateazanavir, cisapride, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, telithromycin, troleandomycin, voriconazole
    17. Grapefruit juice can substantially inhibit CYP3A4 for 24-48 hours
  8. P450 E (MEOS)
    1. alcohol (ethanol)
  9. Note: SSRIs inhibit nearly all CYP classes [3]
    1. Fluoxetine, fluvoxamine, nefazodone and paroxetine are most potent inhibitors
    2. Sertraline and venlafaxine are least inhibitory
  10. Omeprazole and CYP2C19 Mutations [5]
    1. Omeprazole is metabolized by CYP2C19
    2. Specific mutations in CYP2C19 can lead to reduction in omeprazole metabolism rate
    3. Homozygosity for slow metabolizer mutations leads to increased exposure to omeprazole
    4. Omeprazole 20mg qd + amoxicillin 1gm bid led to 100% eradication in slow metabolizers

I. Monoamine Oxidase (MAO)navigator

  1. Distribution
    1. Liver
    2. Kidney
    3. Intestine
  2. Substrates
    1. Catecholamines - dopamine, norepinephrine (NE) and epinephrine (adrenaline)
    2. Tyramine
    3. Phenylephrine
    4. Tryptamine and serotonin (5-hydroxytryptamine, 5-HT)

J. Polymorphisms in Drug Metabolizing Enzymes (DME) [10,11]navigator

  1. A large number of polymorphisms in DME and drug targets have been discovered
  2. A subset of these polymorphisms lead to reduced or increased DME activity
  3. P450 Mutations of Clinical Importance
    1. Poor metabolizers: CYP 2C9 (1%), CYP 2D6 (25% of whites, 2-8% blacks, 1% Asians)
    2. Ultrarapid metabolizers: gene duplication of CYP 2D6 (5% whites, 2% blacks, 1% Asians)
  4. Slow acetylators (NAT-2 mutant) are very common (>40% whites, >50% blacks, >10% Asians)
  5. Drug Target Polymorphisms
    1. ß-Adrenergic receptor mutations leading to decreased response to ß2-agonists
    2. Sulfonylurea receptor mutations leading to reduced insulin response to sulfonylureas
  6. Transporter and Channel Polymorphisms
    1. Mutations in mdr1 transporter gene
    2. Mutations in long QTc syndrome genes (LQ 1-5) for cardiac ion channels

K. Notes on Specific Compounds [7,16]navigator

  1. Metabolism of Alcohol
    1. Alcohol dehydrogenase (ADH)
    2. Microsomal ethanol-oxidizing system (MEOS; induced by EtOH)
    3. Acetaldehyde, highly reactive with biomolecules, is produced
    4. Normally, acetaldehyde is converted to acetate by aldehyde dehydrogenase (Ald-DH)
    5. Polymorphic Ald-DH leads to reduced enzyme activity and higher acetaldehyde levels [4]
  2. Warfarin [16]
    1. Metabolized by CYP2C9
    2. Polymorphisms in CYP2C9 account for much of the variation in warfarin responses
    3. Also metabolized by vitamin K epoxide reductase (VKORC)
    4. Variants of VKORC subunit 1 (VKORC1) also account for a significant variation in warfarin responses
  3. Drugs Increasing Warfarin Action
    1. Antibiotics - erythromycin, fluconazole, miconazole, isoniazide, metronidazole
    2. Cardiac drugs - amiodarone, propafenone, propranolol, sulfinpyrazone
    3. Other - omeprazole, cimetidine, alcohol, phenylbutazone, piroxicam, theophylline
  4. Drugs Decreasing Warfarin Action
    1. Antibiotics - griseofulvin, nafcillin, rifampin
    2. CNS Agents - barbiturates, carbamazepine, chlordiazapoxide
    3. High vitamin K foods (eg. cruciferous vegetables)
    4. Other: cholestyramine, sucralfate
  5. Drugs Affecting Digoxin
    1. Increase: quinidine, amiodarone, erythromycin, propafenone, verapamil, spironolactone
    2. Decrease: sulfasalazine, cholestyramine, antacids
  6. Drugs Affecting Cyclosporine
    1. Warfarin completely inactivates cyclosporin but warfarin is not affected
    2. Grapefruit juice increases activity
    3. Diltiazem increases activity
  7. Predictions of drug interactions using in vitro derived data are inexact [7]

References navigator

  1. Wilkinson GR. 2005. NEJM. 352(21):2211 abstract
  2. Evens WE and McLeod HL. 2003. NEJM. 348(6):538 abstract
  3. Richelson E. 1997. Mayo Clin Proc. 72(9):835 abstract
  4. Wall TL, Peterson CM, Peterson KP, et al. 1997. Ann Intern Med. 127(5):376 abstract
  5. Furuta T, Ohashi K, Kamata T, et al. 1998. Ann Intern Med. 129(12):1027 abstract
  6. Gregg CR. 1999. Am J Med. 106(2):227 abstract
  7. Drug Interactions. 1999. Med Let. 41(1056):61 abstract
  8. Fugh-Berman A. 2000. Lancet. 355(9198):134 abstract
  9. Thum T ande Borlak J. 2000. Lancet. 355(9208):979 abstract
  10. Roses AD. 2000. Lancet. 355(9212):1358 abstract
  11. Meyer UA. 2000. Lancet. 356(9242):1667 abstract
  12. Phillips KA, Veenstra DL, Oren E, et al. 2001. JAMA. 286(18):2271
  13. Nebert DW and Russell DW. 2002. Lancet. 360(9340):1155 abstract
  14. Rogers JF, Nafziger AN, Bertino JS Jr. 2002. Am J Med. 113(9):746 abstract
  15. Weinshilboum R. 2003. NEJM. 348(6):529 abstract
  16. Roden DM, Altman RB, Benowitz NL, et al. 2006. Ann Intern Med. 143(10):749
  17. Drug Interactions. 2003. Med Let. 45(1158):46 abstract
  18. Markowitz JS, Donovan JL, DeVane CL, et al. 2003. JAMA. 290(11):1500 abstract
  19. Drug Interactions with Grapefruit Juice. 2004. Med Let. 46(1773):2
  20. CYP3A and Drug Interactions. 2005. Med Let. 47(1212):54 abstract