Monday, 17 April 2023

Drug Biotransformation

Terms and De nitions:

* Biotransformation — mechanism, by which the body terminates the action of some drugs, it is a
combination of some pharmacokinetic principles, which serve to transform the drug for it to
become more easily excreted.

Outcomes of Biotransformation:
(1) Activation of a prodrug.

(2) Conversion of lipophilic drugs into more hydrophilic ones, which helps in drug excretion by the
kidney.

(3) Formation of active/toxic metabolites.

Phase I VS Phase II reactions:

Biotransformation of drugs occurs mainly in the liver, via Phase I and Phase II reactions, this
processes help lipophilic drugs to become more hydrophilic:

Phase Reactions of the phase

* Oxidations

* Epxidations

* Dealkylations

* Deamination

Phase I - oxidation reactions

* Desulfuration

* Cytochrome P450-dependent oxidations

* Reductions

* Hydrolysis

* Glucoronidation

* Acetylation

* Glutathione conjugation

Phase II - conjugation reactions * Glycine conjugation

* Sulfation

* Methylation

* Water conjugation
In some cases, phase II reactions precede the phase I reactions: Isoniazid - drug for tuberculosis,
rstly undergoes phase II and then phase I reactions.

Phase I reactions occur with help of

CYTP450.

* Step 1 — oxidized (Fe+3) P450

combines with a drug substrate to form a
binary complex

* Step 2 — NADPH donates an electron to

the avoprotein P450 reductase, which in
turn reduces the oxidized P450-drug
complex.

* Step 3 — A second electron is

introduced from NADPH via the same
P450 reductase, which serves to reduce
molecular oxygen and to form an
“activated oxygen”–P450–substrate
complex

*Step 4 — This complex in turn transfers

activated oxygen to the drug substrate to form the oxidized product.

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 Monday, 17 April 2023
Human liver CYP450 system - are a superfamily of enzymes containing heme as a cofactor that
function as monooxygenases

- Most important enzymes of this system and their concentrations in the liver are:

* CYP3A4/5 — 30% — accounts for metabolism of ~ 50% of drugs.

* CYP2D6 — 5%

* CYP2C8/9 — 20%

* CYP2B6 — 1%

* CYP2A6 — 4%

* CYP2E1 — 10%

* CYP1A2 — 15%

Metabolism of acetaminophen: analgesic,

antipyretic drug.

NAPQI - toxic product, which is neutralized by

glutathione.

If overdose by acetaminophen occurs

Administration of N-acetylcysteine within 8–16
hours after acetaminophen overdosage protect
from fulminant hepatotoxicity and death,
because N-Acetylcysteine donates glutathione
and neutralizes NAPQI.

Enzyme Induction

- Some of the chemically dissimilar P450 substrate drugs, on repeated administration, induce P450
expression by enhancing the rate of its synthesis or reducing its rate of degradation.

- Induction results in accelerated substrate metabolism and usually in a decrease in the

pharmacologic action of the inducer and also of co-administered drugs.

- However, in the case of drugs metabolically transformed to reactive metabolites, enzyme induction
may exacerbate metabolite-mediated toxicity.

- Increased P450 synthesis requires enhanced transcription and translation along with increased
synthesis of heme, its prosthetic cofactor.

- P450 enzymes may also be induced by substrate stabilization, eg, decreased degradation, as is
the case with troleandomycin- or clotrimazole-mediated induction of CYP3A enzymes, the
ethanol- mediated induction of CYP2E1, and the isosafrole-mediated induction of CYP1A2.

Inducers of liver enzymes:

* Rifampin

* Carbamazepine

* Phenobarbital and other Barbiturates

* Phenytoin

* St. John’s wort

* Smoking

* Chronic alcohol consumption

Enzyme inhibitors:
* Cimetidine

* Ketoconazole

* Itraconazole

* Erythromycin

* Allopurinol

* Ethanol(acute alcohol consumption)

* Disul ram

* Grapefruit juice

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