Biotransformation of xenobiotics







After chemical modification, the more hydrophilic compounds are excreted into the urine, bile,
sweat. They can also occur in the milk.

Volatile products are breathed forth.

Under certain conditions, compounds excreted into the bile can undergo deconjugation and absorption
(the enterohepatic circulation).



It proceeds in two phases:

Phase I  - the polarity of the compound is increased by introducing a polar group (hydroxylation is
a typical reaction), increase in polarity by another way, or demasking a polar group (e.g., by
hydrolysis of an ester or dealkylation of an amide or ether).

     The reactions take place predominantly on the membranes of

     endoplasmic reticulum, some of them within the cytoplasm.

     The first phase reactions may convert some xenobiotics to the compounds that are more
biologically active than the xenobiotic itself.

 Phase II  – Cytoplasmic enzymes catalyze conjugation of the functional groups introduced in the
first phase reactions with a polar component

     (glucuronate, sulfate, glycine, etc.). These products are mostly less biologically active than
the substrate drug, the xenobiotic is detoxified.













Allelic variation that effects the catalytic activity of monooxygenases will also affect the
pharmacologic activity of drugs.

Example of such polymorphism is that of the isoform CYP 2D6: there are

    extensive metabolizers (most of normal population),

    poor metabolizers (5 – 10 % of normal individuals), and

    rapid metabolizers (individuals who rapidly metabolize debrisoquine as

      well as a significant number of other commonly used drugs).

In the group of rapid metabolizers – the plasma levels of drugs are higher than expected, unwanted
side effects are oft.

In the group of rapid metabolizers – lower drug plasma levels than expected after usual doses, the
treatment is ineffective. To obtain satisfactory results, the drug doses have to be higher than
those used in extensive or poor metabolizers.



























It is proper to avoid application of too many different remedies together, though their expected
effects can be viewed as useful.

   – Interactions between different drugs or their metabolites might   cause enhancement or
inhibition of pharmacological effects,

   – the mixed type hydroxylases (cyt P450) are inducible, their activities

      may increase many times in several days, so that the remedies

      are less efficient,

   – if the load of the detoxifying system is high, minor pathways of     transformation can be
utilized and produce unwanted side-effects

      due to the formation of toxic metabolites,

   – intensive conjugation with glutathione might result in depletion of this

      important reductant in the cells, etc.









New tests have been developed (unfortunately, they are not yet used commonly in

routine laboratory practice), which are able to detect not only when a person drank last time, but
also if the doses taken were moderate or excessive.

Fatty acids ethyl esters (FAEE) appear in the blood in 12 – 18 h after drinking and can be detected
even 24 h after alcohol in blood is no more increased. However, traces of FAEEs are deposited in
hair for months and may serve as a measure of alcohol intake.

Ethyl glucosiduronate (EtG) increases in the blood synchronously with the decrease of blood ethanol
and can be detected (in the urine, too) after few days, even up to 5 days.

Phosphatidyl ethanol (PEth) is present in the blood of individuals, who have been drinking moderate
ethanol doses daily, in even 3 weeks after the last drink.

Carbohydrate-deficient transferrin (CDT). In the saccharidic component of each transferrin
molecules, there are 4 – 6 molecules of sialic acid. Drinking to excess disturbes the process of
transferrin glycosylation so that less sialylated forms of transferrin (with only two or less
sialyl residues per molecule, CDT) are detected in blood during approximately 4 weeks after
substantial alcohol intake.