biotransformation of drugs

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Drug metabolism, prodrug biotransformation


  • Biotransformation of DrugsSeptember 10, 2007Frank F. Vincenzi

  • Learning objectives: drug biotransformationXenobiotic, endoplasmic reticulum & microsomesFirst pass effect, bioavailabilityPro-drug, parent compound, metabolite (active or inactive)Lipophilicity vs. hydrophilicityCytochrome P-450 (CYP1A2, CYP2C9 CYP2C19, CYP2D6, CYP2E1, CYP3A4* )Phase I vs. phase II drug metabolism(debrisoquine) polymorphismExtensive and poor metabolizers

  • Really fundamental concepts in drug biotransformationLipid soluble drugs are poorly excreted in the urine. They tend to store in fat and/or circulate until they are converted (phase I biotransformation) to more water soluble metabolites or metabolites that conjugate (phase II biotransformation) with water soluble substances.Water soluble drugs are more readily excreted in the urine. They may be metabolized, but generally not by the CYP enzyme systems.

  • Biotransformation & urinary excretionDrugs with major first pass effect (bioavailability) [% urinary excretion] imipramine (39)[
  • Evolution of drug metabolizing enzymesTerrestrial life necessitated a substantial increase in the capacity and generality of how to deal with environmental xenobiotics*, including compounds present in food. * compounds not normally present in a particular living system, foreign compounds

  • Major biotransformation sitesLiver


  • Mixed function oxidases (monooxygenases) Cytochrome P450s or CYPs)Add one atom of molecular oxygen to a drug substrate, another to protons to form water.Are linked by NADPH-cytochrome P450 reductase* to the oxidation of NADPH to NADP+Have relatively low substrate selectivity; drugs may be metabolized by more than one CYP; the common characteristic is lipophilicity

    *also called NADPH cytochrome c reductase

  • A simple minded view of the liver endoplasmic reticulum (microsomes)

  • Phase I biotransformation reactions*Oxidation (mainly by mixed function oxidases)

    Reduction Hydrolysis *may result in inactivation, activation, or no change in pharmacological potency/activity

  • Various enzymes involved in metabolism of drugs

  • Metabolism of codeine (normal)

  • Phase II biotransformation reactions*Acetylation Glucuronidation Glutathione conjugation Sulfation *almost always result in decreased potency and half life (notable exception morphine-6-glucuronide ~ 100 x more potent than morphine - may be created in the brain)

  • Patient caseDonny Oregoni 12 y/o white male treated with low dose imipramine for behavior problems and enuresis. Rx for 1 month, renewable 3x.At three weeks Donny complains of tiredness, weakness.At the end of a month of treatment, Donny feels poorly; Stepmother gives Donny a warm bath; he collapses and diesImipramine plasma level in Donny was >> 1 mg/L (therapeutic 0.1-0.3 mg/L)

  • Genetic polymorphism ofdrug metabolizing enzymesDonny - had abnormal CYP2D6; about 3-10% of whites, autosomal recessive

    Abnormal CYP 2D6 is also known as debrisoquine polymorphism - such patients are slow metabolizers, also called poor metabolizers of debrisoquine Some drug list items metabolized by 2D6: carvedilol, cevimeline, chlorpheniramine, efavirenz, imipramine, metoprolol, promethazine and timolol)

  • Graphical representation of what happened to Donny Oregoni

  • CYP2D6 deficiency also affects metabolism of codeine

  • Therapeutic drug monitoringPotentially lifesavingParticularly important anytime dosage is changed or drugs are added or withdrawn ExpensiveFor some drugs, there is no simple relationship between plasma level and therapeutic effect

  • GeneChip* CYP450 Assay(applied pharmacogenomics)A matrix on a chip (high density miniaturized array of oligonucleotides) that can identify the CYP phenotype of a patient. By the year 2000 enabled rapid detection of 18 known mutations of CYP2D6 and CYP2C19. Could easily do hundreds.In 2005 Roche AmpliChip CYP 450 Test was approved. Cost estimated at that time was about $950 - cost will come down significantlySomething like this is likely to become a part of initial patient screening in the near future. *

  • Patient CaseRoberto Bolli, 22 y/o white male treated with theophylline for control of asthma. Stable on theophylline for 8 years.Transient skin infection - prescribed 10 doses of ciprofloxacin to be taken over 5 days.At the end of day 5, Roberto was treated in the ER for headache, nausea & vomiting and sent home. Theophylline level not determined.Later that night, status epilepticus - theophylline level >60 mg/L (10-20 mg/L therapeutic); permanent brain damage.

  • Inhibition of biotransformation: A basis for many different kinds of drug interactionCiprofloxacin (and many other compounds) inhibit CYP enzyme(s) involved in the metabolism of theophylline (CYP1A2 &/CYP3A4)

    Roberto Bolli represents a tragic, but all too common, case of drug interaction. Many Rx drugs alter biotransformation. Even grapefruit juice contains an inhibitor of CYP3A4.

  • Increased bioavailability of some drugs in patients who drink grapefruit juice

  • Induction of drug biotransformation: Another basis of various drug interactionspolycyclic aromatic hydrocarbons, etc. - CYP1A2 phenobarbital - CYP2C9ethanol - CYP2E1 phenytoin - CYP3A4glucocorticoids, macrolide antibiotics (erythromycin, etc.), anticonvulsants - CYP3A4

  • Some consequences of enzyme inductionSmokers metabolize theophylline faster than non-smokers - polycyclic aromatic hydrocarbons induce CYP1A1

    Chronic consumption of alcohol induces CYP2E1 - promotes pharmacokinetic tolerance

    CYP3A is inducible by macrolide antibiotics, some steroids and some anticonvulsants - may increase metabolism of a wide variety of drugs

  • Examples of Substrates, Inhibitors and Inducers of CYPs

  • Patient case, Heidi Raines, day 1Heidi Raines: 33-year-old white female, previously healthy. Two days ago developed a bad headache with nausea and vomiting. Yesterday developed a stiff neck and was told over the telephone to take Extra-Strength Excedrin according to directions on the bottle. Today made an ER visit (Dr. W) and was treated with Demerol for headache pain and, finally, was able to rest. She was felt to have a migraine and a skeletal headache and was sent home with a prescription for Demerol tablets (50 mg tabs, 1-2 q 3-4 h prn pain). Her husband was very concerned about her and wanted to do all that he could to help.

  • Heidi Raines, day 2Mrs. Raines was seen (by Dr. X) in the Clinic with headache, stiff neck, nausea, and vomiting. Demerol was stopped, and she was treated with Darvon without help. Continue Extra-Strength Excedrin, 2 e 4 h prn pain.

  • Heidi Raines, day 5Day 5: Mrs. Raines was seen in the Clinic (by Dr Y) and was given a prescription of Midrin* (1 stat, then 1 q 3 h, prn). Her husband was beginning to show increased anxiety concerning her welfare. He said she had not really eaten for days because of this 'sick headache'. Once again he was reassured, and was told that he could help by taking care of her at home. He promised to be helpful.

    *Isometheptene, 65 mg Dichloralphenazone, 100 mg Acetaminophen, 325 mg

  • Heidi Raines, day 6Day 6: Mrs Raines continued her medications and seemed to improve, although she had been unable to keep any food down for about one week. Her headache worsened and on a Clinic visit (Dr. Z) she was treated with Meprobamate and three Extra Strength Tylenol and was sent home with instructions to take three Extra Strength Tylenol every 3-4 hours, prn. Same old story with the husband.

  • Heidi Raines, day 7Day 7: Continuing medications as prescribed, Mrs. Raines felt somewhat better on the day prior to admission with little headache, nausea or vomiting. However, she then developed crampy abdominal pain, anorexia, and nausea and, as per a telephone conversation, was treated with DiGel, but, because of persistent symptoms, was admitted to the hospital.

  • Heidi Raines, day 8Physical exam on admission showed a thin, 33-year-old, cigarette smoking, white female complaining of abdominal pain, nausea, vomiting, and headache. She talked in a weak voice. Her neck was supple. The chest was clear. The heart showed a sinus rhythm. There was some abdominal tenderness with no rigidity and no masses. The patient appeared pale and rather drowsy, but had no focal neurologic findings.

  • Heidi Raines, hospital courseLiver enzymes were massively elevated with SGOT over 20,000 units. Fibrinogen level became nondetectable and platelet count continued to fall. Hematocrit and hemoglobin dropped. Bilirubin stayed stable around 3.2 mg%. Creatinine rose from 2.5 to 3.5 mgm%. The BUN was 9 or 10 mg%. Total protein was 4.5 with albumin of 3.1 grams%. Blood ammonia was 239 mg%. Neurologically, the patient deteriorated and became unresponsive. The cause of death was felt to be a respiratory arrest with subsequent cardiac arrest on the basis of severe massive hepatic necrosis (emphasis added) with metabolic changes and metabolic encephalopathy.

  • Heidi Raines: Autopsy1.Acute massive necrosis of the liver2.Severe metabolic acidosis, lactic acidosis, treated.3.Acute pulm. edema, with interalveolar hemorrhage4.Diffuse intravascular coagulation.5.Acute renal failure secondary to acute tubular necrosis.6.Metabolic encephalopathy, secondary to hepatic coma7.Metabol. acidosis severe lactic acidosis, H20 depletion8.Anemia, ? hemolytic, ? due to blood loss into lungs.

  • Why did Heidi Raines die?Failure to properly diagnose and treat

  • The hus


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