Liver Detoxification and Excretion PDF

Royal College of Surgeons in Ireland Medical University of Bahrain Liver: detoxification and excretion  Learning objectives Define pharmacokinetics and describe the main purpose of drug metabolism, identifying principal sites Describe the types of reaction involved in phase I drug metabolis...

Royal College of Surgeons in Ireland Medical University of Bahrain Liver: detoxification and excretion  Learning objectives Define pharmacokinetics and describe the main purpose of drug metabolism, identifying principal sites Describe the types of reaction involved in phase I drug metabolism with examples Describe the metabolism of ethanol and explain the mechanism of action of disulfiram Describe the types of conjugation reactions involved in phase II drug metabolism Describe the metabolism of aspirin and paracetamol and explain why some drugs (e.g. paracetamol) are toxic at high doses Define prodrugs and recall situations in which these are used Describe drug-drug interactions Pharmacokinetics Pharmacokinetics is the study of how drugs move into, around and out of the body – “what the body does to the drug” So what is pharmacodynamics? Key components: – Administration – Distribution – Metabolism – Elimination What is Drug Metabolism? In drug metabolism, generally Metabolism is the process whereby drugs in the body undergo transformations catalysed by enzymes. The products are called metabolites Lipophilic drugs Hydrophilic metabolites. not excreted excretable Water solubility results in increased renal excretion and decreased tubular reabsorption. Possible Consequences of metabolism: Formation of an inactive polar metabolite Formation of an active metabolite Formation of a toxic metabolite Site of Drug Metabolism The liver is the principal organ of drug metabolism Liver cells contain efficient enzymes for metabolism of foreign materials Other tissues which are active include the gastrointestinal tract, lungs (volatile substances), skin and kidneys Consequences of Drug Metabolism Drug can be converted to an excretable form (structure that easily cleared by kidney) Drug action can be terminated Drug can be converted to a metabolite which has pharmacological action of its own An inactive “pro-drug” can be converted to an active drug Metabolism of foreign compounds (xenobiotics) Elimination in urine Phase I (without “conjugation”) Phase II (conjugation) Functional groups such as -OH, -NH2, Available functional groups in a -COOH introduced or ‘unmasked’ into drug molecule (which may or may drug molecule not result from phase I) are Main function of phase I metabolism conjugated with hydrophilic groups. is to prepare drugs for phase II Increases water solubility and ease metabolism of excretion Drug Metabolism CYTOCHROME P450 HYDROXYLATE “MANY” XENOBIOTICS The reaction catalyzed by a cytochrome P450 is as follows: RH above can represent a very wide variety of xenobiotics; drugs, carcinogens, pesticides, petroleum products, and pollutants. In addition, endogenous compounds, such as certain steroids, eicosanoids, fatty acids, and retinoids, are also substrates. CYTOCHROME P450 HYDROXYLATE MANY XENOBIOTICS parent daughter Cytochrome P450 cycle in drug oxidations. RH, parent; ROH, oxidized metabolite; e–, electron. Phase I Oxidation Reactions Example: Hydroxylation Hydroxylation Involves addition of an - OH group. It is a type of oxidation. Lidocaine Lidocaine P-450, NADPH, O2 Local anaesthetic which is metabolized by hydroxylation Phase I Oxidation Reactions Example: Oxidative Dealkylation + Codeine Morphine Methanal Codeine (10%) is de-alkylated to morphine Produces an analgesic effect Other Phase I reactions reduction, hydrolysis reduction chloramphenicol hydrolysis aspirin salicylate acetate Chloramphenicol is an antibacterial Aspirin is an analgesic; inhibitor of COX Phase I Oxidation Reactions Example: Dehydrogenation Most ethanol is metabolized by the liver. The next step is to further oxidise the acetaldehyde to acetate Complete metabolism of ethanol cytosol mitochondrion Oxidation of the acetaldehyde occurs enzymatically in the mitochondria. It relies on the enzyme aldehyde dehydrogenase (ALDH). Acetate is then released to the blood for subsequent oxidation to CO2 by other tissues. Disulfiuram Used in the management of alcoholism Alcohol mainly metabolized in the liver to acetaldehyde by alcohol dehydrogenase (ADH) which is then oxidized to acetate by aldehyde dehydrogenase (ALDH). Disulfiram acts as an irreversible inhibitor of Aldehyde dehydrogenase. Disulfiram causes a 5- to 10-fold increase in the concentration of acetaldehyde which produces unpleasant side effects: – facial flushing, nausea, vomiting, dizziness, and headache Metabolism of ethanol by alcohol dehydrogenase and the microsomal ethanol-oxidizing system (MEOS). MEOS uses NADPH and consists primarily of CYP450 2E1, 1A2, and 3A4. When large amounts of ethanol are consumed, the alcohol dehydrogenase system becomes saturated (depletion of NAD+). During chronic alcohol consumption, MEOS activity is induced. As a result, chronic alcohol consumption results in significant increases not only in ethanol metabolism but also in “Genetic disulfiram” Deficiency in the activity of the ALDH the clearance of other drugs (common among East Asians) eliminated by the cytochrome Phase II Metabolism A hydrophilic group is conjugated to the molecule giving a water soluble product. Often, Phase I metabolism provides conjugation site (eg OH) Then excreted in bile or urine. Conjugation catalyzed by transferase enzymes Main reactions are – Glutathione conjugation – Glucuronic acid conjugation – Sulfate conjugation – Glycine conjugation – Acetylation Phase II Metabolism Main conjugation reactions are : – Glutathione conjugation – Glucuronic acid conjugation Most common form of conjugation, Common for drugs with -OH, -COOH, -NH2 groups – Sulfate conjugation Common for phenols – Glycine conjugation Common for drugs with –COOH groups – Acetylation Conjugation with glucuronic acid Most common form of conjugation Product is a “glucuronide” Common for drugs with -COOH, -OH, -NH2 groups Glucuronic acid is transferred from UDP-glucuronic acid by glycuronyl transferase Conjugation with Sulphate Sulphation is common for phenols Sulphate is transferred to the drug from the reactive intermediate 3-phosphoadenosine-5’- phosphosulfate (PAPS), by sulfotransferase. Glucuronide formation and sulfation often compete for the same substrate e.g. paracetamol. Conjugation using glutathione Detoxification products containing sulphur – Sulphur atom derived from glutathione – an unusual cysteine-containing tripeptide (glutamate-cysteine-glycine; Glu-Cys-Gly) – End product – Mercapturate Foreign compounds include:- – Aromatic nitro- and halogenated compounds – Phase l oxidation products of polycyclic hydrocarbons Conjugation with Glycine Common for drugs with –COOH groups (e.g. low dose aspirin pathway – see next slide) Metabolism of Aspirin Metabolism of paracetamol Paracetamol and two primary metabolites are relatively non-toxic hepatotoxicity is due to 5% that is oxidised to: benzoquinoneimine, a highly reactive substance – normally combines with glutathione – when glutathione stores depleted free benzoquinoneimine combines with hepatic proteins and causes liver injury Paracetamol Normally undergoes glucuronidation and sulfation to the corresponding conjugates, which together make up 95% of the total excreted metabolites. The alternative P450-dependent GSH conjugation pathway accounts for the remaining 5%. When intake far exceeds therapeutic doses, the glucuronidation and sulfation pathways are saturated, and the P450- dependent pathway becomes important. antidotes—cysteamine or N- acetylcysteine within 8–16 hrs after overdosage. Administration of GSH is not effective because it does not cross cell membranes readily. Alcohol abuse and paracetamol toxicity CYP1A2, CYP2E1 and CYP3A4 are induced by ethanol. Alcohol abusers have four-fold higher levels of these enzymes in their livers over non-drinkers. CYP1A2, CYP2E1 and CYP3A4 are the p-450 isoforms which oxidise paracetamol to benzoquinonamine (toxic). When these CYP450 enzymes are induced by alcohol, a greater amount of paracetamol is converted to benzoquinonamine. Hence in alcohol abusers, toxicity can occur much lower levels of paracetamol (only slightly greater than recommended doses) Cytochromes P450 Subfamily Family name Cytochrome P 450 CYP2D6A Pigment Absorbs light “pink” At 450nm Specific protein Different allelic forms ~60 human P-450 enzyme systems identified Knowledge of P-450 system important in understanding drug metabolism and drug interactions. Many of the enzymes have broad substrate specificity Person-person variation in CytP450 genes is responsible for many unexpected adverse drug reactions CYP3A4/5 and UGT, are involved in the metabolism of more than 75% of drugs in use Relative contributions of various cytochrome P450 isoforms (A ) and different phase II pathways (B ) to metabolism of drugs in clinical use. Many drugs are metabolized by two or more of these pathways. DPYD, dihydropyrimidine dehydrogenase; GST, glutathione-S-transferase; NAT, N-acetyltransferase; SULT, sulfotransferase; TPMT, thiopurine methyltransferase; UGT, UDP-glucuronosyltransferase. Prodrugs A prodrug is a pharmacologically inert precursor to an active drug Activation of a prodrug usually involves a phase I reaction enzymes Prodrug Active drug Administration elimination DMEs DMEs Pro- Active Drug- Drug Drug Metabolite CYP2D6 No Benefit CODEINE MORPHINE in 10% patients Approx. 10% null for CYP2D6 Possible reasons to use a prodrug 1. Overcome drug instability 2. Site-specific drug delivery 3. Improved physicochemical properties 4. Prolonged drug release 5. To encourage patient acceptance 1. Overcome drug instability Cefamandole sulfate is a broad spectrum antibiotic that is difficult to purify and is unstable The ester formed between cefamandole sulfate and methanoic acid is pure and stable; it is cleaved by esterases in the blood to give the active drug esterase Methanoic acid Cefamandole sulfate Cefamandole sulfate-methanoic acid ester Cefamadole Naftate (kefadol) 2: Site Specific Drug Delivery 1 Sulfasalazine is the drug of Azo linkage choice for ulcerative colitis The active therapeutic moiety is 5- aminosalicylic acid (5-ASA) but this, if administered directly, cannot reach the colon due to absorption at prior sites. sulfasalazine However Sulfasalazine, which can reach the in colon, colon, contains 5-ASA linked to azoreductases sulfapyridine by an azo linkage which is broken down by azoreductases in the colon. H2 + H 2 5-Aminosalicylic acid (5-ASA) sulfapyridine (active therapeutic moiety) (carrier for 5-ASA but responsible for adverse affects of sulfasalazine) 2: Site Specific Drug Delivery 2 Diamorphine (heroin) Prodrug used to deliver morphine to the central nervous system The –OH groups of morphine are acetylated in diamorphine this is more lipophilic than morphine crosses the blood-brain barrier more readily Diamorphine acetyl groups are removed (ester esterases hydrolysis) in the CNS to give morphine. Blood-Brain Barrier + CH3COO- morphine O 3: improved physicochemical properties esterase Enalaprilat is an ACE inhibitor However Enalaprilat is poorly absorbed because of its polarity The ethyl ester of Enalaprilat i.e. Enalapril is less polar and better absorbed. It is metabolised by esterase enzymes in vivo to the active drug Enalaprilat. 4: slow and prolonged drug release prodrugs can be particularly important in the treatment of psychoses where medication over long periods is required and there is high non-compliance Haloperidol Haloperidol is a potent orally active CNS depressant used to treat psychotic disorders and schizophrenia Dose: 1 to 2 mg 2 or 3 times daily. Haloperidol decanoate Haloperidol decanoate is an ester prodrug. It is injected intramuscularly and the antipsychotic activity lasts for 1 month due to slow conversion to haloperidol. It is used mainly to treat schizophrenia. 5: to encourage patient acceptance Sulfioxazole is an antibacterial sulfa drug that is very bitter tasting Sulfioxazole acetyl is tasteless; deacetylated to the active form Summary of drug metabolism Medical Pharmacology at a Glance, M. J. Neal