Amna Medani , 2015

DRUG METABOLISM

It is the metabolic alteration of drug molecules . This

usually involves two types of biochemical reactions

that occur sequentially in two phases known as phase

(ǀ) and phase (ǁ). Phase I reactions usually involves

oxidation ,reduction ,hydrolysis , deamination and

dealkylation reactions. This may render the

descendant drug more active and some times more

toxic than the parent drug (functionalization phase).

Amna Medani , 2015

Phase II reactions involve conjugation reactions which render the

drug inactive . Both stages will decrease the lipid solubility of the

drug and hence , Increase its renal elemination assissted by the non-

selective detoxification system of the intracellular metabolizing

enzymes.

This takes place mainly in the liver except for some drugs where the

two phases occur in the plasma (e.g. hydrolysis of suxamethonium

and procaine by plasma cholinesterases) , in the lung (e.g. various

prostanoids) or in the wall of intestines (e.g. tryptamines ).

 

Amna Medani , 2015

The liver intracellular enzymes are mostly attached to

the smooth endoplasmic reticulum (microsomal

enzymes) sediment after prolonged high speed

centrifugation on homogenization. A non-polar

drug ,more readily ,can pass the hepatocyte membrane

and reach these enzymes where as the highly polar

drugs , if they do not have a carrier system , may be

excreted unchanged.

Amna Medani , 2015

Phase I Reactions

A/ Oxidation Reactions :

(Hydroxylation of nitrogen and carbon atoms , N- and O-

dealkylation and oxidative deamination) are catalyzed by

the enzymatic system mixed function oxygenase system

that resides on the endoplasmic reticulum ( e.g.

cytochrome P-450 that catalyze hydroxylation

reactions) .

Amna Medani , 2015

Some drugs may be metabolized by:I / The soluble cytoplasm enzyme alcohol dehydrogenase (e.g. ethanol) .II/ The non-microsomal enzyme xanthine oxidase (involoved in uric acid synthesis and inactivation of the cytotoxic drug 6-mercaptopurine).III/The monoamine oxidase enzyme ( involved in the inactivation of many active amines e.g. tyramine and noradrenaline ) which can occur in many tissues other than the liver.

Amna Medani , 2015

B/ Reduction Reactions:

I/ The anticoagulant drug warfarin is inactivated by the

conversion of a ketone group to a hydoxyl one .

II/ Many steroids (e.g. cortisone and prednisone) are

activated by the reduction of the ketone group to the

corrosponding hydroxy compounds. These also

involves microsomal enzymes . 

Amna Medani , 2015

C/ Hydrolytic Reactions:

These occur only in tissues other than the liver to

hydrolyse the ester and amide groups (e.g. hydrolysis of

procaine by the plasma cholinesterases).

Amna Medani , 2015

Phase II ReactionsA drug may be susceptible to a conjugation reaction ( attachment of a substituent group), if it has a handling group (e.g. a hydoxyl , a thiol or an aminogroup) . The conjugate is pharmacologically inactive and less lipid soluble than the precursor ( from phase I ) is then excreted. This conjugate formation is often involoving a glucuroynly- , a glycyl- , a sulphate- , a methyl- , an acetyl- or a glutamyl- group in the liver ,mostly , lung or kidney .

Amna Medani , 2015

I/Glucronide formation involves the formation of a high energy phosphate group (Uridine Diphospho-Glucuronic Acid ) from which the acid part is changed into an electron rich atom ( N-,O- OR S- ) forming and amide- , ester or thiol- bonds catalyzed by glucuronyl-transferase.

II/ Acetylatin and methylation reactions occur with acetyl co-A and S-adenosyl methionine respectively.

Amna Medani , 2015

Induction of Microsomal Enzymes:

Many drugs can enhance the activity of microsomal enzymes and

the conjugateing system (e.g. ethanol,phenobarbitone and

phenylbutazone) as well as some carcinogenic substances (e.g.

benzpyrine ) . This can result from an increase of :

I/ Microsomal enzymes synthesis.

II/ The rate of metabolism of inducing agent in variable patterns

(e.g. phenobarbitone is a verstile , non-selective inducer that

increase the rate of degradation of many drugs and polycyclic

hydrocarbons are selective only to oxidase enzyme ). Induction to

phase I metabolism can increase the drug effect.Phase I induced

metabolites may cause toxicity ( e.g. paracetamol and the

carcinogenic polcyclic hydrocarbons).

Amna Medani , 2015

Mechanism: This is suspected to involve stimulation of gene transcription leading to incearsed protien synthesis by binding to cytosolic recteptor that in turn binds to to specific DNA sequences associated with the production of particular drug metabolizing enzymes. First-pass metabolism ( Presystemic ):-Much larger dose of the drug is required orally.-Marked individual variation occur in the extend to which a drug can be metabolized.

 

Amna Medani , 2015

Renal Excretion of Drugs & Drug Metabolites

-The kidneys handle different dugs differently (e.g.

penicillin is excreted completely after a single passage

through the kidney , where as the chlorpromazine is

excreted slowly and all the drugs excretion rates fall

between these two ranges).

-The products of phases I and II are excreted more

readily than the parent drug.

Amna Medani , 2015

-The basic processes incorporated in renal excretion are :

I/ Glumerular Filteration :

- This allows all drugs of molecular weight less than

20000 with a concentraction in the filtrate nearly similar

to that in plasma.Drugs bound to plasma protiens ( plasma

albumin molecular weight = 68000) are less readily found

in the filterate (e.g. phenylbutazone concentrations is 98%

bound to plasma albumin and its concentration in the

filtrate is 2% only )

Amna Medani , 2015

II/ Tubular Secretion & Reabsorption:

-20% of a drug is removed from blood via glumerular filtration ,whereas the remainder 80% moves to the pretubular capillaries of the proximal tubules to reach the two independent , non-selective carrier systems ( one can transport acidic drug and the other is specific for basic substances) to be taken to the tubular lumen against an electrochemical gradient-Many drugs excreted via kidneys share the same carrier system and hence , compitition occur ( e.g. probencid retard the excretion of penicillin and inhibit the reabsorption of uric acid , but it is useful in the treatment of gout ).

Amna Medani , 2015

III/ Diffusion Across Renal Tubules: -Water is reabsorbed in the renal tubules ( urine volume is 1% of that of the filtrate).drugs with micromolecules are readily filtered in the renal tubules( plasma concentration – filtrate concentration) and hence , it can easily be absorbed passively.Drugs with high lipid solubility and high tubular permeability are also slowly excreted.

Amna Medani , 2015

-Highly polar drugs have high urine concentrations (e.g. gallamine and streptomycin).-Weak acids and bases change their ionization and hence, markedly affect excretion ( a basic drug may be readily excreted in an acidic urine ( e.g. gaptamine )and an acidic drug can not be reabsorped if the urine is alkaline ( e.g. barbiturate and aspirin) due to ionization.

 

Amna Medani , 2015

Drug Clearance : It is the volume of plasma containing the amount of substance that is removed by the kidney in a unit time : CLr = CU VU/CP

Where : CLr = Clearance of a drug.

Cu = Drug urinary concentration.

Vu = Rate of flow of urine.

  Cp = Drug plasma concentration.

Amna Medani , 2015

Factors Affecting Drug Clearance :-Drugs that are completely filtered (not protien-bound) may have a clearance almost similar to the glumerular filteration (e.g. insulin CLr = 120 ml / min. ).

-Drugs that are completely excreted via the carrier system of the renal tubule during a single passage through the kidney (e.g. penicillin ) ,may have a CLr

nearly equal to that of P-amiohippuric acid which is equal to renal plasma flow (700 ml/min. ).

Amna Medani , 2015

-Drugs that are excreted via passive diffusion (e.g. barbiturates) may have a CLr nearly equal to the rate of urine formation (1ml / min. ).-Clearance varies among individuals and from time to time in the same individual thus, affecting the values of drug safety.

Amna Medani , 2015

Billiary Excretion :The transference of drugs and drug metabolites from plasma to bile through liver cells. TRANSPORT SYSTEMS:I/ Acid and base handling systems.II/ Transport of unchanged molecules.

Amna Medani , 2015

-Various hydrophilic drugs conjugates are delivered

into the intestines , hydrolized and then released to

be reabsorbed and recycled again ( e.g. digoxin,

morphine ,chloramphenicol and stilbosterol).

- Some drugs are considerably excreted in bile (e.g.

cromoglycate in the unchanged form and rifambicin

in the deacetylated form).