1. BIOTRANSFORMATION, Drug metabolism, detoxification
netversion

2. Fate of Xenobiotics Enzymatic conversion
Elimination without any chemical reaction
Spontaneous chemical conversion
Accumulation without conversion

3. Cellular metabolism of xenobiotocs
1st phase
2nd phase
3rd phase

5. phase I metabolism – purpose: „function groups” are formed
Oxidation
Reduction
Hydrolysis
Hydratation
Formation of a more polar metabolite than the original substrate, better chance for excretion, lipid soluble → water soluble

6. Cytochrome P450 system flavoprotein lipid – (membrane – SER)
hemoprotein
Flavoprotein:
NADPH – P450 oxidoreductase
Lipid:
phosphatidyl choline
Hemoprotein:
Cytochrome b5
Cytochrome P450
Reductase – P450 ratio: 1 : : 100

8. Role of the liver in drug metabolism
-first pass effect – one way street – chemical factory
Portal circulation

9. Cytochrome P450 gene superfamily
In mammals 8 families, in drug metabolism 4: CYP1, CYP2, CYP3, CYP4
Expressed mainly in liver, but also in lungs, intestines, skin and kidneys
Gene evolution, protein filogenesis – natural selection – survival value
Ancestor gene 3,5 bilion yrs (22 exon),
1,5 bilion yrs ago: plant ↔ animal separation,
400 million yrs ago: surface ↔ ocean

10. 1.5 billion yrs
400 million yrs
today

11. Figure 3. Contribution of major human P450s to the Phase I metabolism of all drugs currently marketed (25). The compilation is intended to be approximate and will vary with changes in drugs. For tables of raw data see Rendic (22). The non-P450 enzymes include alcohol and aldehyde dehydrogenases, flavin-containing monooxygenases, etc.

12. CYP 1 2 genes even 100 fold inducibility Inducers: metilcholantrene
dioxin derivatives
industrial technologies
environmental pollution
cigarette smoke
Inducibility incidence of bronchial arcinoma
Substrates:
Policyclic aromatic carbohydrates (PAH): benzpyrene, benzanthracene etc.
Medicines: teophyllin, phenacetin etc.

13. CYP 2 (A – H) Inducers: phenobarbital Ethanol Aceton
Diazepam derivatives
CYP 2A steroids, testosteron
CYP 2B progesteron, D3 vitamin, antiepileptics
CYP 2C mephenytoin - antiepileptics
CYP 2D antidepressants, beta blockers, antihypertensive agents,
debrisoquine metabolism
PM poor metabolizer
EM extensive metabolizer
Inducibility gastrointestinal tract carcinomas,
bronchial carcinoma incidence
CYP 2E etanol, aceton
diabetes mellitus, starvation

14. Figure 1. Relative rates of CYP2D6 activity in a Caucasian population (4). CYP2D6 activity is represented as the ratio of unmetabolized drug (here, debrisoquine) to drug metabolite (4-hydroxydebrisoquine) collected from the urine following a single dose. The distribution is the result of the existence of more than seventy alleles in the population (see Early research labeled individuals as "extensive metabolizers" (green) and "poor metabolizers" (blue) (5). The "ultrarapid metabolizer" phenotype (red) can result from inherited gene amplification

15. Figure 4. Significance of unexpectedly low metabolism of a drug by P450s. The typical pattern seen with the majority of the population (extensive metabolizers) is shown in the upper panel, where the plasma level of the drug is maintained in a certain range over the period of several consecutive doses (arrows indicate multiple doses). Unusually slow metabolism (lower panel) occurs when a poor metabolizer (without previous knowledge of phenotype) receives the same dose, resulting in an elevated plasma level of the drug. Adapted from

16. CYP 3 Inducers: steroids Oral contraceptives
PCN – pregnenolon carbonitril
Substrates:
Antibiotics
nifedipin
cyclosporin

17. CYP 4 Inducer: clofibrate – antihyperlipemic agent Substrates:
Fatty acids
eicosanoids