Biotransformation of drugs

Transcription

1 Biotransformation of drugs (Drugmetabolism) PharmDr. Pavol Ježko, PhD. Department of Pharmaceutical Chemistry Faculty of Pharmacy, Comenius University dbojarov 10, Bratislava, Slovakia Tel: jezko@fpharm.uniba.sk; p.jezko@gmail.com 1

2 Biotransformation of drugs biochemical modification / degradation of drugs drugsare partially eliminated unchanged or partially biotransformedby metabolic pathways and are excreted as metabolites biotransformation of drugs influences the deactivation, activation, detoxification, and toxification of the vast majority of drugs 2

3 BJECTIVE: conversion of lipophilicdrugs to more polar compounds that are easier eliminated 3

4 XENBITICS substances that do not naturally occur in the body(theyenter the body), are not necessary for the physiological development and have no nutritional value drugs agrochemicals pesticides, herbicides, fertilizers food additives flavoring agents, coloring agents, preservatives, stabilizers 4

5 Placesofdrugbiotransformation liver: the majority of metabolic reactions kidney: 2. phase guts: 2. phase blood(ester hydrolysis) plasma(hydrolysis of esters) within a cell(organels): endoplasmic reticulum(microsomes) enzymes cytochrome P450 (CYP-450) mitochondria cellcytosol 5

6 CNSEQUENCES of BITRANSFRMATIN bioinactivation: usually products are less active or inactive metabolites bioactivation: in some cases, the metabolic process converts non-active substance on its own active form (prodrug) 6

7 TYPES F BITRANSFRMATINREACTINS Biotransformation of drugs takes place in two steps: first phase - functionalization reactions the molecule introduces a new functional group, usually polar(-c,-,-nh2) the polar group can serve as a reaction point for the second reaction phase second phase- conjugation reactions addition of endogenous molecules (glucuronic, sulphate) to the metabolite of 1. phase prerequisite for conjugation reactions is the presence of a suitable chemical group (-C,-,-NH2) results of both phases are metabolites more soluble in water, and easier elimininated 7

8 Reactions of 1 phase drug metabolism Type of reaction The reaction pathway xidation Reduction Hydrolysis aromatic or aliphatic hydroxylation N- or S-oxidation N-, - or S-dealkylation ReductionN 2 group to hydroxylamine and amine Reduction of the carbonyl to alcohol Ester on acid and alcohol Amid on acid and amine

9 Reaction of 2 phase drugmetabolism Type ofreaction Endogenousreagentor substrate Glucuronic conjugation Uridine-diphosphate of glucuronic acid(udpgt) Xenobiotic substrate Carboxylicacid, alcohol, phenol, amine Sulfate conjugation 3 -phosphoadenosine-5 - Alcohol, phenol, amine phosphosulfate (PAPS) Acetylation Acetyl-CoA Amine Glutathione conjugation glutathione Epoxides, compounds with chlorine atom Methylation S-adenozylmethionine Phenols, amines, thiols Amino acid conjugation Glycine, glutamine Carboxylic acid

10 1. XIDATIN incorporation ofpolar groupsin thedrug moleculeorsubstitution ofonepolargroupby another to increase the polarization 10

11 1. a) xidation of alkyl-compounds most common type ofoxidationon the side-alkyl chain(ifacompound has aliphatic, aromatic or heterocyclic character) oxidationusuallybeginson the lastcarbonthrough the primary alcoholic group and proceed finally to acid can take place on the penultimate carbon(betaxidation),whicharemetabolised type offatty acidcompoundsin the body 11

12 oxidation of pentobarbital H N N H CH 3 CH 3 CH 3 H N N H CH 3 CH 3 CH 3 H N N H CH 3 CH 3 H 2 C H N N H CH 3 CH 3

13 1. b ) xidation alkohols, aldehydes, acids aliphatic primary alkohols light oxidation of (prim. drug) to aldehydes(c, sec. metab.) and to the acid(-c, final metab.) ľahká oxidácia cez aldehydy ( C) až na kyseliny ( C) tertiary are notso much metabolized mainly are creating glucuronide conjugates 13

14 1. c) xidativehydroxylationof of aromatic compounds (rings) phenolicsubstancesare produced,the final metabolite is eliminatedas a conjugate with glucuronic acid or sulfuric acid, which is well soluble in water phenolic substances are produced 14

15 1. d) xidativen and and dealkylationdealkylation common reaction on ethers andalkylamino-drugs etheric bondis quite strong, sosimplealiphatic ethers areoftenexcretedunchanged,thecomplex ethers are metabolisedpartially only phenolic ethers are cleaved to the phenolic part and aldehyde. 15

16 drugscontaininga tertiaryor secondaryamine ( NH 2 ) are partiallymetabolizedto secondaryand primary amines,and aldehyde it is assumed thatn-metyl-derivates aredealkylated throughthen-oxides andn-hydroxymetyl-derivates by the scheme: 16

17 1. e) xidation to N oxids (N oxidation) drugs withtertiary amino-group 17

18 1. f) xidativedeamination drugs, which contains the primaryaliphatic aminesare metabolisedby monoamine oxidase(ma). These reactions vary according to the nature of the amine. phenylethylamine- type drugs are oxidized to aldehyde and acid and ammonia: substances like aryl-isopropylamine are oxidized to ketone 18

19 1. g) xidation to sulfoxideand andsulfone phenothiazines 19

20 1. h) xidative desulfurization thesulfuratom will be refundfor oxygenatom in drug molecule (S ) (some thiobarbiturates are oxidized to barbiturates) 20

21 1. i) xidativedehalogenation halogenated compounds are converted to acid halothane is partially metabolised by the scheme DDT, pesticide 21

22 1. j) xidativeopening of the ring complete destruction of the drug molecule 22

23 1.k) xidation of double bonds 23

24 2. REDUCTIN reduction takes place in liver microsomes,in the presence of reductase function groups: nitro andazo-groups, aldehydes, ketones, arsenic compounds 24

25 2. a) Aromatic nitro-compounds are reduced (in the presence of nitro-reductase) to aromatic amines (as intermediates can be nitroso- a hydroxylamines derivates) amino-compounds are excreted as acetyl-derivates 25

26 2. b)azo-compounds are reduced(in the presence of azo-reductase) to aromatic amines (probably in the first step is produced hydrazo-benzene) 26

27 2. c) Aldehydes and ketones aldehydes are reduced to primary ketones are partly eliminated unchanged in somecasesare reducedtosecondary,andare excretedfrom the body in the form of glucuronic acid conjugate 27

28 cyclic ketones compounds which contains arsenic 28

29 3. HYDRLYSIS REACTINS reactions, in which substances with a functional group is broken down into simpler products A. hydrolysis of esters B. hydrolysis of amides C. hydrolysis of anilides D. hydrolysis of nitriles E. hydrolysis of carbamates 29

30 3. a) Hydrolysis of esters all esters are splited by esterase on the acid and alcohol part hydrolysis of esters is realised in blood or in liver (depends on drug character) 30

31 3. b) Hydrolysis of anilides first is N-dealkylation, next step is hydrolysis of anilide bond 31

32 3. c) Hydrolysis of amides by amidase (in the liver) 32

33 3. d) Hydrolysis ofnitriles on the acid (only with aromatic derivates) 33

34 3. e) Hydrolysis of carbamates 34

35 4. CNJUGATINREACTINS condensation reaction metabolic reactions in which the drug, respectively its metabolite with hydroxyl (), carboxyl (C) or amino (NH2) group in the body is conjugated with hydrophilic -the body's own compound: glucuronic acid, sulphate, glycine, acetic acid, etc. according to the nature body chemicalcomponent, wecandivide conjugate condensation reactions to conjugation: A. glucuronic B. sulfate C. amino acid D. acetylation E. methylation 35

36 4. a) Glucuronic conjugation glucuronicacid reactswithdrugscontaininghydroxyl(, phenols), carboxylic, sulphydryl(sh) and partially amino group glucuronic conjugation mechanism- a reaction occurs between the metabolite and glucuronic acid in the active form glucuronic acid reacts in the activated form as uridinediphosphateglucuronicacid(udp), -bindsto thedrugswiththeactivesemiacetylhydroxylgroup, itmeans with hydroxyl group bound to the phosphoric acid H H H H P P H N N Kyselina uridine uridín-difosfoglukurónová diphosphate glucuronic (UDP-glukurónová) acid

37 UDP reacts with the alcohol (with long aliphatic chains)or phenoland forms ether-glucuronides H H H H UDP + R H H H H R ether-glucuronide Éterglukuronid examples: menthol, borneol, camphor, paracetamol, morphine, estriol

38 UDP reacts with the aliphatic or aromatic carboxyl-groups and forms ester-glucuronide H H examples: H H UDP + R C benzoic acid, salicylic acid, acetylsalicylic acid H H H H R ester-glucuronide Esterglukuronid UDP forms with aromatic amines N-glucuronides UDP forms with sulfhydryl groups S-glucuronides UDP forms conjugates also with the body's own substances such as steroid hormones

39 4.b) Sulfate conjugation process occurs in the liver few-steps process active agent: 3 -phosphoadenosine- 5 -phosphosulfate aliphatic and aromatic hydroxyl-groupdrugs( and phenols) and aromatic amine compounds drugs: mainly derivates of phenol, cresol, naphthol; morphine, etc. body's own substances such as hormones (estrone, androsteron) 39

40 4.c) Amino acids conjugation reaction: acid reacts with amino acids in the active form -binding to coenzyme A (CoA) R CoA-SH R S CoA + N H 2 R N H + CoA-SH N-acyl-glykokol

41 4.d) Acetylation closely related to the amino acids conjugation, as acetylation agent is acetylcoenzyme A, which reacts with the amino group of the drug reaction occurs in the liver and kidneys acetylation is important conjugation reaction, especially for drugs with a prim. amino group (histamine, p-aminobenzoic acid, sulfonamides) 41

42 4.e) Methylation this conjugation reaction is unique in humans (common reaction in animals) common reaction with primary andsecondary amines, unique at drugswith hydroxyl or sulphydryl group donor of the methyl group is activated S-adenosyl methionine: most common methylation is reaction with catecholamines(adrenaline, noradrenaline), histamine, nicotinic acid ) N-methylation pyridin derivates morphine, codeine, barbiturates S-methylation mercaptopurine, dimercaptopropanol 42

43 PRDRUG inactive prodrug form is metabolised in organismon on the active drug form 43

44 Strategiesfordevelopment ofprodrug prodrugform improvement of solubility or better preparation ofdrugform improvement of peroral absorption and distribution high specifity and lower toxicity stability or prolongation of drug release better tolerance by patients protectiong group must be stable against stomach acid and enzymes, but after absorption should be sufficiently labile, for release of active drug form (metabolite) 44

45 Metabolizms of selected drugs eliminated without changes (2 22%) C CCH 3 C conjugation with glycine CNHCH 2 C 45-91% Acetylsalicyl acid Salicyl acid C esters and ether glucuronids H Gentisic acid 2-4%

46 H N CCH 3 ox. NHCCH 3 -glucuronide 60% -sulphate 30% NHCCH 3 glutathion Paracetamol Acetaminophen cleavage intermediate NHCCH 3 p-aminophenol (nephrotoxic) paracetamol cysteine N-acetyl-benzoquinoneimine S C C H C H2 NH 2 hepatic peptides NHCCH 3 NHCCH 3 paracetamol mercapturate S peptidy hepatotoxic metabolite S C H2 C H C NHCCH 3

47 Me CMT HC C H2 NH 2 in CNS HC CH 2 MA in the periphery CMT Me HC C H2 NH 2 HC CH HC C HC C Noradrenaline (Norepinephrine) CMT Me HC C H2 Adrenaline (Epinephrine) NHCH 3 HC C H2 NHCH 3

48 Theendend no drug is metabolised only byone pathway, but there are more of this pathways atthethe same time so, for the drug metabolims, there areno general rules e.g. sulphonamides are metabolised side by side with oxidative hydroxylation and next step is sulphate conjugation, next reaction is acetylation, the mutual relationship of metabolites may vary according to the total amount of drug metabolized e.g. small amount of phenole-derivate is eliminated by conjugation with sulphate, but whenthere isanexcessofphenole-derivatesin thebody,there isthehigherpartof its conjugate with glucuronic acid 48

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