Pharmacology for Dentistry

Pharmacokinetics 31

formation of drugs to more polar and less
lipid soluble metabolites enhances their
excretion and reduce their volume of
distribution. The primary site of drug
metabolism is liver. The other organs like
kidney, intestine, lungs and plasma are also
involved in drug metabolism.

Many active drugs, during metabolism
are converted into one or more active metabo-
lites and produce effect due to the collective
effect of parent drug and their metabolites
e.g. phenacetin is converted into paracetamol,
phenylbutazone into oxyphenbutazone,
primidone into phenobarbitone, amitrip-
tyline into noriptyline, imipramine into
desimipramine and codeine into morphine.
Certain drugs (parent drug) are inactive as
such and has little or no biological activity
called ‘prodrug,’ but it is metabolized to a
pharmacologically active compound. For
example, levodopa is converted into
dopamine which is effective in the treat-
ment of parkinsonism, the anticancer drug
cyclophosphamide is biologically inert but
is converted into a active cytotoxic com-
pound aldophosphamide, and another an-
ticancer drug fluorouracil is changed into
fluorouridine monophosphate, etc.

The drug metabolism in liver usually
undergoes three general types of enzymatic
reactions:

1. Oxidation-reduction and hydrolysis or
   stage I reaction.


2. Conjugation or stage II reaction.
   The first stage I reaction i.e. oxidation-
   reduction are generated by a common
   hydroxy-lating enzyme system (cytochrome
   P450 system; CYP), which is located in

endoplasmic reticulum of the liver cells. The

CYP important isoenzymes in human being

are CYP3A4/5, CYP2C19, 2CYP2D6,

CYP2C8/9, CYP2E1 and CYP1A1/2 which

are responsible for metabolism of large

number of drugs. Hydrolytic enzymes are

mostly located in the cell cytoplasm or in

plasma and conjugation enzymes are

associated with cytoplasm and endoplasmic

reticulum.

OXIDATION

Oxidative reactions involve addition of

oxygen/negatively charged radical or

removal of hydrogen/positively charged

radical.

The different oxidative reaction are:

Hydroxylation

It may be followed by oxidation to form a

ketone or in the case of oxidative dealkylation

to form an unstable intermediate, examples

are:

Ring : Phenobarbital in to p-hydroxypheno-

hydroxylation barbital.

Cortisol into 7-β-hydroxycortisol.

Epoxidation : Benzene into benzene 1,2-epoxide.

N-oxidation : Drug containing amino groups can

undergo N-oxidation i.e. imipra-

mine into imipramine N-oxide.

O-dealkylation : This reaction probably involves

formation of an unstable hydroxy

methyl intermediate i.e. codeine

into morphine.

Oxidative : Amphetamine into phenylpropa-

deamination none-2.

REDUCTION

The different type of reduction reactions

are azo, nitro and keto group reductions.

The important one is azoreduction, and

example includes conversion of prontosil