Lesson 3 Jezko Biotransformation of Drugs

8/13/2019 Lesson 3 Jezko Biotransformation of Drugs

1/48

Biotransformation of drugs

PharmDr. Pavol Jeko

Center of Excellence PharmacyDepartment of Medicinal Chemistry

CADD Laboratory

Faculty of Pharmacy, Comenius University

Odbojarov 10, 832 32 Bratislava, Slovakia

Tel: + 421 250 117 221

e-mail: [email protected];[email protected]


2/48

Drug metabolizms it is a biochemical modification or degradation of

drugs

drugs are partly eliminated unchanged or partiallyi r n f rm m li h n r

excreted as metabolites

drug metabolism is also of great importance in

medicinal chemistry because it influences (inqualitative, quantitative, and kinetic terms) thedeactivation, activation, detoxification, andtoxification of the vast majority of drugs

2


3/48

OBJECTIVEOBJECTIVE::

conversion of lipophilic

compounds that are easier

eliminated


4/48

XENOBIOTIXENOBIOTICSCS

substances that do not naturally occur in the body

(that enter the body ), are not necessary for thephysiological development and have no

drugs (health)

agrochemicals (agriculture) pesticides, herbicides, fertilizers

food additives

flavoring agents, coloring agents, preservatives, stabilizers

4


5/48

Places of drug biotransformation liver: the majority of metabolic reactions

kidney: 2 phase guts: 2 phase

blood (ester hydrolysis)

lasma h drol sis of esters

within a cell:

endoplasmic reticulum (microsomes)

enzymes cytochrome P450 (CYP-450)

mitochondria

cell cytosol


6/48

CONSEQUENCES

ofBIOTRANSFORMATION

bioinactivation:

usually products are less active or inactive

bioactivation:

in some cases, the metabolic process converts

non-active substance on its own active form(prodrug)

6


7/48

TYPES OF BIOTRANSFORMATION

REACTIONS

drug metabolism takes place in two steps:

first phase - functionalization reactions the molecule introduces a new functional group, usually polar (-COOH,-OH,-NH2)

the polar group can serve as a reaction point for the second reaction phase

second phase - conjugation reactions includes the addition of endogenous molecules (glucuronic, sulphate) to the

metabolite of 1 phase

(prerequisite for conjugation reactions is the presence of a suitable chemical group(-COOH,-OH,-NH2)

results of both phases are metabolites more soluble in water ,

and thus easier elimininated


8/48

Type of reaction The reaction pathway

Oxidation aromatic or aliphatic hydroxylationN- or S-oxidation

N-, O- or S-dealkylation

Reactions of 1 phase drug metabolism

Reduction Reduction NO2 group to hydroxylamine andamine

Reduction of the carbonyl to alcohol

Hydrolysis Ester on acid and alcoholAmid on acid and amine

Hydrazide on acid and substituted hydrazine


9/48

Type of reaction Endogenous reagent or

substrate

Xenobiotic substrate

Glucuronidation Uridine-diphosphate of

glucuronic acid (UDPGT)

Carboxylic acid, alcohol,

phenol, amine

Sulfation 3-phosphoadenosine-5-

Alcohol, phenol, amine

Reaction of 2 phase drug metabolism

phosphosulfate (PAPS)Acetylation Acetyl-CoA Amine

Glutathione

conjugation

glutathione Epoxides, compounds

with chlorine atom

Metylation S-adenozylmethionine Phenols, amines, thiols

Aminoacid Glycine,glutamine Carboxylic acid


10/48

1. OXIDATION1. OXIDATION incorporation of polar groups in the molecules of the drug or substitution

of one polar group by another for increase of the polarization

according to the character of reaction, metabolic oxidation is dividedinto several types:A. Oxidation of alkyl-compounds

B. Oxidation of alcohols aldeh des acids

C. Oxidative hydroxylations of aromatic compoundsD. Oxidative N and O dealkylation

E. Oxidation to Noxids

F. Oxidative deamination

G. Oxidation of sulfids to sulfoxids and sulfonesH. Oxidative desulfuration

I. Oxidative dehalogenation

J. Oxidative opening of the ring

10


11/48

1. a) Oxidation of alkyl1. a) Oxidation of alkyl--compoundscompounds it is the most common type of oxidation on the side-alkyl chain (if

a compound has aliphatic, aromatic or heterocyclic character)

drugs containing aliphatic unbranched alkyls are

easily oxidized; oxidizing of alkyls decreases with ramifications of the

alkyl chain

oxidation usually begins on the last carbon through

the primary alcoholic group and proceed finally to acid

can take place on the penultimate carbon (beta-

oxidation), which are metabolised type of fatty acid compounds in the

body11


12/48

oxidation of pentobarbital: metabolites with prim.

aliphatic hydroxyl or carboxyl group at the terminal methyl group

are produced; or the sec. alcoholic group on the penultimate carbon

atom of the alkyl is metabolised

NH

CH3

O

NH

CH3

O

NH CH

3

3

O

NH CH

3

3

O OH

NH

NH

O

CH3

C

H2

CH3O

O

OH

NH

NH

O

CH3

CH3O

O

OH

O


13/48

1.1. b )b ) Oxidation alkohols, aldehydes, acidsOxidation alkohols, aldehydes, acids

aliphatic primary alkoholsaliphatic primary alkohols

light oxidation of alcohols (prim. drug) to aldehydes (COH, sec. metab.)

and to the acid (-COOH, final metab.)

ahk oxidcia cez aldehydy (COH) a na kyseliny (COOH)

tertiary alcohols are not so much metabolized

mainly are creating glucuronide conjugates

13

alcohols


14/48

1.1. c)c) OxidatOxidativeive hydroxylhydroxylationation ofof aromaticaromatic

compoundscompounds ((ringsrings))

phenolic substances are produced, the final metabolite is eliminated as

a conjugate with glucuronic acid or sulfuric acid, which is well soluble in water

14

phenolic substances are produced


15/48

1.1. d)d) OxidativeOxidative NN andand OO dealkylationdealkylation

common reaction on ethers and alkylamino-drugs

etheric bond is quite strong, so simple aliphatic ethersare often excreted unchanged, the complex ethers are metabolised partially only

phenolic ethers are cleaved to the phenolic part and aldehyde.

15

alcohols

alcohols


16/48

drugs containing a tertiary or secondary amine (NH2) are

partially metabolized to secondary and primary amines, andaldehyde

it is assumed that N-metyl-derivates are dealkylatedthrough the N-oxides and N-hydroxymetyl-derivates by the

scheme:

16


17/48

1.1. e)e) OxidationOxidation toto NNoxids (Noxids (Noxidation)oxidation)

drugs with tertiary amino-group

17

alcohols


18/48

1. f) Oxidative deamination drugs, which contains the primary aliphatic amines are metabolised by monoamineoxidase (MAO). 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

18alcohols


19/48

1.1. g)g) OxidationOxidation ofof sulfides to sulfoxidssulfides to sulfoxids

andand sulfonessulfones

thioethers type drugs - this type of biotransformation is

common in the group of phenothiazines

19

alcohols


20/48

1.1. h)h) Oxidative desulfurizationOxidative desulfurization

some sulphur-compounds are oxidized by oxidative desulfurization,

the sulfur atom will be refund for oxygen atom in drug molecule (S O)

(some thiobarbiturates are oxidized to barbiturates)

20

alcohols


21/48

1. i) Oxidative dehalogenation

halogenated compounds are converted to acid

halothane is partially metabolised by the scheme

DDT

21

alcohols

alcohols


22/48

1. j) Oxidative opening of the ring

complete destruction of the drug molecule

22


23/48

1.k) Oxidation of double bonds

alcohols

alcohols


24/48

2. REDUCTION2. REDUCTION uncommon metabolic pathway

reduction takes place in liver microsomes, in the presence ofreductase

function groups: nitro and azo-groups, aldehydes, ketones,arsenic compounds

24


25/48

2. a) Aromatic nitro2. a) Aromatic nitro--compoundscompounds 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


26/48

2. b)2. b) AzoAzo--compoundscompounds are reduced (in the presence of azo-reductase) to aromatic amines

(probably in the first step is produced hydrazo-benzene)

26alcohols

alcohols

alcohols


27/48

2. c) Aldehydes and ketones2. c) Aldehydes and ketones aldehydes are reduced to primary alcohols

alcohols

ketones are partly eliminated unchanged

in some cases are reduced to secondary alcohols, and are excreted from the

body in the form of glucuronic acid conjugate

27alcohols


28/48

cyclic ketones

alcohols

compounds which contains arsenic

alcohols


29/48

3.3. HYDROLYHYDROLYSSIISS REACREACTTIIONSONS 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


30/48

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

alcohols


31/48

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

31

alcohols

alcohols alcohols


32/48

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

32

alcohols

alcohols


33/48

3. d) Hydrolysis of nitriles on the acid (only with aromatic derivates)

33

alcohols


34/48

4. C4. CONJUGAONJUGATIONTION REACREACTIONSTIONS condensation reaction

metabolic reactions in which the drug, respectively its metabolite with hydroxyl

(OH), carboxyl (COOH) or amino (NH2) group in the body is conjugated with

hydrophilic - the body's own compound : glucuronic acid, sulphate, glycocoll,

, .

according to the nature body chemical component, we can divide conjugate

condensation reactions to conjugation:

A. glucuronic

B. sulfate

C. glycocollic

D. acetylation

E. methylation

34


35/48

4. a)4. a) GlucuronicGlucuronic conjugationconjugation

glucuronic acid reacts with drugs containing hydroxyl (alcohols, phenols),

carboxylic, sulphydryl (SH) and partially amino group

glucuronic conjugation mechanism - a reaction occurs between the metaboliteand glucuronic acid in the active form

glucuronic acid reacts in the activated form as

uridine diphosphate glucuronic acid (UDP),

- binds to the drugs with the active semiacetyl hydroxyl group, it means

with hydroxyl group bound to the phosphoric acid

N

N

OO

OH

H

OH

OH

H

OH

HH

O

OHO

P O P O

O

OH

O

OH

OH OH

O OH

Kyselina uridn-difosfoglukurnov (UDP-glukurnov)uridine diphosphate glucuronic acid


36/48

UDP reacts with the alcohol (with long aliphatic chains) or phenol and forms

ether-glucuronides

O

OH

H

OH

OH

H

OH

HH

O

OHO

R OH

O

OH

H

OH

OH

H

OH

HH

O

OHO

UDP

+

R

terglukuronid

examples:

menthol, borneol, camphor, paracetamol, morphine, estriol

ether-glucuronide


37/48

UDPUDP reactsreacts withwith the aliphatic or aromatic carboxyl-groups and forms

ester-glucuronide

O

OH

H

OHOH

H

OH

HH

O

OHO

R COOHO

OH

H

OHOH

H

OH

H

H

O

OHO

O

R

Esterglukuroni

UDP +

examples:ester-glucuronide

benzoic acid, salicylic acid, acetylsalicylic acid

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


38/48

4.b) Sulfate conjugation sulfate conjugation is conneted with

aliphatic and aromatic hydroxyl-group-

drugs (alcohols and phenols) andaromatic amine compounds, which

provide sulfamates

3-phosphoadenosine-

5-phosphosulfate

own process occurs n t e ver

it is few-steps process and sulphonation,

and agent in the final phase works

3 -phosphoadenosine-5-phosphosulfate

sulfate conjugation of the drug are

eliminated mainly phenolic nature such

as phenols, cresols, naphthols,

morphine, etc.

by sulfate conjugation are

eliminated some of the body's own

substances such as hormones

(estrone, Androsteron)


39/48

4.c)4.c) GlycocollicGlycocollic condenzationcondenzation

by this way are predominantly metabolised aromatic acid as conjugation ingredients except

glycocoll (glycine) also apply to amino acids (cysteine, ornithine, glutamine)

reaction: acid reacts with glycocoll or amino acids in the active form, it means binding to

coenzyme A (CoA):

ROH

O

RS

O

NH2

O

OH

R NH

O

OH

O

CoA-SH

N-acyl-glykokol

CoA +

+ CoA-SH


40/48

4.d) Acetylation closely related to the glycocollic 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)

40


41/48

4.e) Methylation this conjugation reaction is unique in humans (common reaction in animals)

common reaction with primary and secondary amines, unique at drugs with hydroxyl or

sulphydryl group

donor of the methyl group is activated S-adenosyl methionine:

most common meth lation is reaction with

catecholamines (adrenaline, noradrenaline),histamine, nicotinic acid )

N-methylation pyridin derivates morphine, codeine, barbiturates

S-methylation mercaptopurine, dimercaptopropanol 41

PRODRUGPRODRUG


42/48

PRODRUGPRODRUG

inactiveinactive prodrugprodrug formform isis metabolisedmetabolised inin organismorganism

onon thethe activeactive drugdrug formform

42

St t iSt t i ff d l td l t


43/48

StrategiesStrategies forfor developmentdevelopment

ofof prodrugprodrug formform improvementimprovement ofof solubilitysolubility oror betterbetter preparationpreparation

ofof drugdrug formform improvementimprovement ofof per osper os absorptionabsorption andand distributiondistribution

stability orstability or prolongationprolongation ofof drugdrug releaserelease

better tolerance by patients

protectiong group must be stable against stomach acidand enzymes, but after absorption should be sufficiently

labile, for release of aktive drug form (metabolite)

43

Metabolizms of selected drugs


44/48

Metabolizms of selected drugs

OCOCH3

COOH

OH

COOH

eliminated without changes (2 22%)

OH

CONHCH2COOH

conjugation

with glycine

Acetyl-

salicyl

acid

Salicyl acid45-91%

OH

COOH

OH

Gentisic acid 2-4%esters and ether

glucuronids


45/48

NHCOCH3

OHOH

NOH COCH3

NHCOCH3

Paracetamol

Acetaminophen

ox.

paracetamol cysteineintermediate

glutathion cleavage

O-glucuronide 60%

O-sulphate 30%

p-aminophenol

(nephrotoxic)

NHCOCH3

OH

NHCOCH3

S peptidy

OH

S C

H2

C COOH

NH2

OH

NHCOCH3

S CH

2

CH

COOH

NHCOCH3

N-acetyl-benzoquinone-imine

hepatic peptides

hepatotoxic metabolite

paracetamol

mercapturate

O

OH OH


46/48

OHOH

OH

CH CH

2OH

NH2

OMe

OH

OH

OH

CH

OH

OH

CH2OH

OHOH

OH

OMe

COMT

COMTMAO

in the periphery

in CNS

CH CH2OH

NH2

OH

CH CH

2OH

NHCH3

OH

OH

CH CH

2OH

NHCH3

OMe

CH

OH

CHO CH

OHCOOH CH

OHCOOH

Noradrenaline

(Norepinephrine)

COMT

Adrenaline(Epinephrine)


47/48

TheThe endend

nono drugdrug isis metabolisedmetabolised onlyonly byby oneone pathwaypathway,, butbut therethere areare

moremore ofof thisthis pathwayspathways atat thethe samesame timetime

so,so, forfor thethe drugdrug metabolimsmetabolims,, therethere areare nono generalgeneral rulesrules

e.g. sulphonamides are metabolised side by side with oxidative hydroxylation and next

ste is sul hate con u ation, next reaction is acet lation, the mutual relationshi 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

when there is an excess of phenole-derivates in the body, there is the higher part of its

conjugate with glucuronic acid

47


48/48

Lesson 3 Jezko Biotransformation of Drugs

Documents

Transcript of Lesson 3 Jezko Biotransformation of Drugs