BIOTRANSFORMATION OF DRUGSPHASE I: OXIDATION

Submitted by:-

STEFFI K. BABU1st MPHARM (PHARMACEUTICS)JSSCP, OOTY

ELIMINATION

BIOTRANSFORMATION

Conversion of drugs from one chemical form to another.

PHASE I

PHASE II

EXCRETION

Drugs or their metabolites are irreversibly transferred from internal to external

environment

XENOBIOTICSAll chemical substances that are not nutrients for the body and

enter the body through ingestion, inhalation, or absorption

METABOLISM

METABOLE = CHANGE

METABOLISING ABILITYliver>lungs >kidneys >intestine >placenta

>adrenals >skin

DRUG METABOLISM Substances can undergo a broad range of reactions

during metabolism. These reactions include for example: oxidation,

reduction, hydrolysis, hydration, conjugation and condensation.

Drug Metabolisation reactions are divided into 2 phases:

1) Phase I reactions which are functionalization reactions

2) Phase II reactions which are conjugation reactions

OH

OSO3H

PHASE I

PHASE II

Functionalisation/asynthetic reaction

Conjugation Reaction/ Synthetic Reaction/ True Detoxification Reaction

BIOTRANSFORMATION RESULTS

• Amphetamine to Phenyl acetone

PHARMACOLOGICAL INACTIVATION

• Amitriptyline to NortriptylineNO CHANGE IN PHARMACOLOGICAL

ACTIVITY

• Paracetamol to N-hydroxylated metabolite

TOXICOLOGICAL ACTIVATION

• Phenacetin to ParacetamolPHARMACOLOGICAL ACTIVATION

• Iproniazid(antidepressant) to Isoniazid(antitubercular)

CHANGE IN PHARMACOLOGICAL

ACTIVITY

METABOLISM CAN BE A USEFUL LEAD MODIFICATION APPROACHThe antihistamine TERBENAFINE

(R=CH3) was removed from drug market because of arrhythmias. Its metabolite FEXOFENADINE is as active, but does not produce arrhythmias.

OXIDATIVE REACTIONS It increases hydrophilicity of xenobiotics by introducing

polar functional groups

These enzymes require both molecular oxygen and reducing agent (NADPH) to effect reaction [hence it is also called as mixed function oxidases]

Rapidly undergo phase2 /Excreted by kidneys

ENZYMES

RH + O2 + NADPH + H+ ROH + H2O + NADP+

This multi enzyme mixed function oxidase system located in the endoplasmic reticulum of hepatic cells

It is composed of an electron transfer chain consisting of 3 components A heme protein – CYTOCHROME P-450

An enzyme – CYTOCHROME P-450 REDUCTASE

It transferes an oxygen

atom to the substrate

•It functions as an electron carrier•Catalyzing the reduction of cytochrome P-450 to the ferrous form by transferring an electron from NADPH

A heat stable lipid component - PHOSPHATIDYLCHOLINE

The most important component is cytochrome P-450

It facilitate electron transfer from NADPH to

cytochrome P-450

The reduced form of this enzyme (Fe++) binds with carbon monoxide to form a

complex that shows maximum absorption at 450nm ; hence the name

Mechanism of Cyt-P450 catalyzed metabolism

P-450 [Fe3+]

(P-450) RH [Fe3+]

(P-450) RH [Fe2+]

(P-450) (O2) RH [Fe2+]

(P-450) (O2

2-) RH [Fe2+]

(P-450) ROH [Fe3+]

RH

e- (NADPH)CYTOCHROME P-450 REDUCTASE

O2(NADH)e-

H+

H2O

ROH

Selected Cytochrome P450 Substrates Debrisoquine sulfate

Its metabolite may induce Parkinsonism. 3-Oxo-1-cyclopentanecarboxylic acid

Substrate used in a study of biohydroxylation with mutants of cytochrome P450 BM-3.

Oxidation of aromatic carbon atoms This reaction proceeds via formation of

intermediate epoxide [arene oxide]

Monosubstituted benzene derivatives can be hydroxylated at ortho meta or para positions Most common----para hydroxylated product

OXIDATION OF OLEFINES It proceeds via formation of epoxide to yield 1,2-

dihydrodiols Epoxide is stable.

OXIDATION OF BENZYLIC CARBON ATOM

Oxidation of alicyclic carbon atoms

REFERENCE

Lohmann W., Karst U., ―Simulation of the detoxification of paracetamol using on-line electrochemistry/liquid chromatogra-phy/mass spectrometry‖, Anal. Bioanal. Chem., 386 (2006) 1701–1708

Oxidation of Aromatic Aldehydes with Tetrabutylammonium Fluoride:Competition with the Cannizzaro Reaction, Kyoo-Hyun Chung,Byung-Chul Moon, Choong Hwan Lim, Jin Pil Kim, Jae Hak Lee, and Dae Yoon Chi

Drug Metabolism, Frank J. Gonzalez, Robert H. Tukey

Biopharmaceutics and Pharmacokinetics, D.M. Brahmankar