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