BIOTRANSFORMATION OF DRUGS PHASE I: OXIDATION

Submitted by:STEFFI K. BABU 1st MPHARM (PHARMACEUTICS) JSSCP, OOTY

PHASE I
BIOTRANSFORMATION Conversion of drugs from one chemical form to another.

ELIMINATION

PHASE II

EXCRETION Drugs or their metabolites are irreversibly transferred from internal to external environment

METABOLISM

METABOLE = CHANGE
XENOBIOTICS All chemical substances that are not nutrients for the body and enter the body through ingestion, inhalation, or absorption

METABOLISING ABILITY liver>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

Functionalisation/asynthetic reaction

PHASE I

OH
PHASE II

OSO3H
Conjugation Reaction/ Synthetic Reaction/ True Detoxification Reaction

BIOTRANSFORMATION RESULTS
PHARMACOLOGICAL INACTIVATION NO CHANGE IN PHARMACOLOGICAL ACTIVITY TOXICOLOGICAL ACTIVATION PHARMACOLOGICAL ACTIVATION CHANGE IN PHARMACOLOGICAL ACTIVITY

Amphetamine to Phenyl acetone

Amitriptyline to Nortriptyline

Paracetamol to Nhydroxylated metabolite Phenacetin to Paracetamol

Iproniazid(antidepressant) to Isoniazid(antitubercular)

METABOLISM CAN BE A USEFUL LEAD MODIFICATION APPROACH

The 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

ENZYMES

Rapidly undergo phase2 /Excreted by kidneys

These enzymes require both molecular oxygen and

reducing agent (NADPH) to effect reaction [hence it is also called as mixed function oxidases]
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
It transferes an oxygen atom to the substrate

An enzyme CYTOCHROME P-450 REDUCTASE

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
It facilitate electron transfer from NADPH to cytochrome P-450

The most important component is 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

ROH RH
P-450 [Fe3+]

(P-450) ROH [Fe3+]

(P-450) RH [Fe3+]
e- (NADPH) CYTOCHROME P-450 REDUCTASE

H2O
H+
(P-450) (O22-) RH [Fe2+] (P-450) RH [Fe2+]

(NADH)e-

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

O2

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

intermediate epoxide [arene oxide]

This reaction proceeds via formation of

 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 chromatography/mass spectrometry, Anal. Bioanal. Chem., 386 (2006) 17011708

Oxidation of Aromatic Aldehydes with Tetrabutylammonium

Fluoride:Competition with the Cannizzaro Reaction, KyooHyun 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