Supervised by :

Dr. Howaida

Prepared by:

Asma Al Malek Khloud Al Mutairi

Norah Al Jebrin Sara Al Dowsari

Shamma Al Hawawi

Drug Detoxification

Drug:

Drug is a chemical substance used in: Treatment Cure Prevention Diagnosis of diseases

For limited duration or for long time

How Drug go out from body ?

Drug Elimination

Metabolism:conversion of one chemical

entity to another.

Excretion:Loss of drug or its

metabolites

The main routes by which The main routes by which drugs and their metabolites drugs and their metabolites leave the body are:leave the body are:-Kidney-Kidney-Hepatobiliary system -Hepatobiliary system -Lungs-Lungs   Most drugs leave the body in the Most drugs leave the body in the urineurine, either , either unchanged unchanged or as or as polar polar metabolitesmetabolites Some drugs are Some drugs are secreted secreted into bile into bile via the livervia the liver But most are But most are reabsorbedreabsorbed from the from the intestine .intestine .

Drug metabolism involves two kinds of biochemical Drug metabolism involves two kinds of biochemical reaction known as reaction known as phase Iphase I andand phase IIphase II reactionsreactions

Phase I reactions:

OxidationReductionHydrolysis

Phase II reactions:Conjugation(e.g. glucuronidation) of a reactive group (often inserted during phase I reaction ) usually forms inactive and readily excretable products.

  Induction of enzymes by other drugs and

chemicals can greatly accelerate hepatic drug metabolism (Drug interaction)

Drug metabolism

Def:Def: Bio-transformations which eliminate Bio-transformations which eliminate the toxicant or prevent its formation the toxicant or prevent its formation

In some cases, detoxification may In some cases, detoxification may compete with toxication for a chemicalcompete with toxication for a chemical

Detoxification can take several Detoxification can take several pathways, depending on the chemical pathways, depending on the chemical nature of the toxic substancenature of the toxic substance

In general, chemicals without functional In general, chemicals without functional groups, such as benzene and toluene, are groups, such as benzene and toluene, are detoxicated in two phasesdetoxicated in two phases

• --initiallyinitially, a functional group such as hydroxyl , a functional group such as hydroxyl or carboxyl is introduced into the molecule, or carboxyl is introduced into the molecule, most often by cytochrome P-450 enzymes.most often by cytochrome P-450 enzymes.

• --subsequentlysubsequently, an endogenous acid such as , an endogenous acid such as glucuronic acid, sulfuric acid, or an amino acid glucuronic acid, sulfuric acid, or an amino acid is added to the functional group by a is added to the functional group by a transferase. With some exceptions, the final transferase. With some exceptions, the final products are in active, highly hydrophilic products are in active, highly hydrophilic organic acids that are readily excreted.organic acids that are readily excreted.

Nucleophiles generally are detoxificated by generally are detoxificated by conjugation at the nucleophilic functional conjugation at the nucleophilic functional group.group.

• Hydroxylated compounds are conjugated by Hydroxylated compounds are conjugated by sulfation or glucuronidation.sulfation or glucuronidation.

• Thiols are glucuronidatedThiols are glucuronidated• Amines and hydrazines are acetylated.Amines and hydrazines are acetylated. These reactionsThese reactions• prevent peroxidase-catalyzed conversion of prevent peroxidase-catalyzed conversion of

the nucleophiles to free radicals the nucleophiles to free radicals • biotransformation of phenols, aminophenols, biotransformation of phenols, aminophenols,

catechols, and hydroquinones to electrophilic catechols, and hydroquinones to electrophilic quinines and quinoneimines.quinines and quinoneimines.

A general mechanism is conjugation A general mechanism is conjugation with the thiol nucleophile with the thiol nucleophile glutathioneglutathione

Specific mechanisms for the Specific mechanisms for the detoxication of electrophilic detoxication of electrophilic substances include epoxide substances include epoxide hydrolyase-catalyzed hydrolyase-catalyzed biotransformation of epoxides and biotransformation of epoxides and arene oxide to diols and arene oxide to diols and dihydrodiols, respectivelydihydrodiols, respectively

Peroxidase-generated free radicals are Peroxidase-generated free radicals are eliminated by eliminated by electron transfer from electron transfer from glutathioneglutathione. This results in the oxidation . This results in the oxidation of glutathione, which is reversed by of glutathione, which is reversed by NADPH-dependent glutathione reductase. NADPH-dependent glutathione reductase. Thus, glutathione plays an important role in Thus, glutathione plays an important role in the detoxication of both electrophiles and the detoxication of both electrophiles and free radicalsfree radicals

11--Toxicants may crush detoxification processes, Toxicants may crush detoxification processes, leading to exhaustion of the detoxication leading to exhaustion of the detoxication enzymes, consumption of their co-substrates enzymes, consumption of their co-substrates or depletion of cellular antioxidants such as or depletion of cellular antioxidants such as glutathione, ascorbic acid, and a-tocopherolglutathione, ascorbic acid, and a-tocopherol..This results in the accumulation of the ultimate This results in the accumulation of the ultimate toxicanttoxicant..

22 - -Liver DiseasesLiver Diseases..33 - -Some conjugation reactions can be reversedSome conjugation reactions can be reversed..

For exampleFor example::22--naphthylamine, a bladder carcinogen, is N-naphthylamine, a bladder carcinogen, is N-

hydroxylated and glucuronidated in liver, hydroxylated and glucuronidated in liver, with the glucuronide excretedwith the glucuronide excreted