3. Biotransformation
■ "Biotransformation is the chemical change (transformation) of a
substance (xenobiotic) within the body”.
ELIMINATION MECHANISMS
■ Physical mechanism: EXCRETION
■ Chemical mechanism: BIOTRANSFORMATION
4.
5. The sites of biotransformation:
■ Predominantly, the liver
The liver contributes to both the presystemic and the systemic
elimination of many drugs.
■ Other tissues, as well. e.g., in intestinal mucosa cells
presystemic elimination of several drugs
■ In renal tubular cells, etc
■ The colon, by bacteria - e.g., azo reduction, hydrolytic
reactions
9. Phase I Reactions
► Convert parent compound into a more polar
(=hydrophilic) metabolite by adding or unmasking
functional groups (-OH, -SH, -NH2, -COOH, etc.)
► Often these metabolites are inactive
► May be sufficiently polar to be excreted readily
– Oxidation – Reduction
– Hydrolytic cleavage
– Alkylation (Methylation)
– Dealkylation – Ring cyclization
– N-carboxylation – Dimerization
– Transamidation – Isomerization
– Decarboxylation
10. Phase II Reactions
– Conjugation with endogenous substrate to
further increase aqueous solubility
– Conjugation with glucoronide, sulfate, acetate,
amino acid
– Phase I usually precede phase II reactions
11. Purpose of biotransformation
• Converts lipophilic to hydrophilic compounds
• Facilitates excretion
Consequences
• Changes in PK characteristics
• Detoxification
• Metabolic activation
Types
Phase I Phase II
Types of reactions Hydrolysis
Oxidation
Reduction
Conjugations
Increase in
hydrophilicity
Small Large
General mechanism Exposes functional group Polar compound added to
functional group
Consquences May result in metabolic activation Facilitates excretion
12.
13.
14. PHASE I BIOTRANSFORMATIONS
CYP is a heme-containing protein embedded in the membranes of the smooth
endoplasmic reticulum (SER),
Origin of the name cytochrome P-450:
Cytochrome: it is a colored intracellular protein
P: it is pink
450: its absorption spectrum has a maximum at 450 nm
15. CYP can also catalyze dehydrogenation,
Surprisingly, CYP may also catalyze reduction
16. Humans have 18 families of cytochrome P450
genes and 43 subfamilies:
CYP2 drug and steroid metabolism
CYP4 Arachidonic acid or fatty acid metabolism
CYP5 Thromboxane A2 synthase
CYP7A Bile acid biosynthesis (7-alpha hydroxylase of steroid nucleus)
CYP7B Brain specific form of 7-alpha hydroxylase
CYP8B
CYP27A
Bile acid biosynthesis
CYP11
CYP19
CYP21
Steroid biosynthesis
CYP17 Steroid biosynthesis (17-alpha hydroxylase)
CYP24 Vitamin D degradation
CYP26A Retinoic acid hydroxylase important in development
CYP39 7 alpha hydroxylation of 24 hydroxy cholesterol
CYP46 Cholesterol 24-hydroxylase
CYP51 Cholesterol biosynthesis (lanosterol 14-alpha demethylase)