METABOLISM OF DRUGS TO TOXIC PRODUCTS & THE CLINICAL RELEVANCE OF DRUG

METABOLISM

Dr Aakifa Javed

• Metabolism of drugs & other foreign chemicals may not always be a harmless biochemical event, leading to detoxification & elimination of the compound.

• INFACT, several compounds metabolically transformed to reactive intermediates that are toxic to various organs.

• Such TOXIC REACTIONS may NOT be apparent at low levels of exposure when alternative detoxification mechanisms are not yet compromised & the availability of ENDOGENOUS DETOXIFYING COSUBSTRATES (i.e, glutathione [GSH] , glucuronic acid, sulfate) is not limited.

• However, when these resources are exhausted, the toxic pathway become more & more stronger & spreads widely, resulting in apparent organ toxicity (carcinogenesis).

• The no of specific examples of such drugs that induced toxicity is expanding rapidly.

• For Instance: “ACETAMINOPHEN” Trade Name: “PARACETAMOL”.• Acetaminophen induced hepatic toxicity.• It is analgesic antipyretic drug & quiet safe in

therapeutic doses of 1.2g/d for an adult.

Normal Mechanism

• “ACETAMINOPHEN” normally undergoes GLUCURONIDATION & SULFATION to the corresponding conjugates w/h makeup 95% of the total excreted metabolites.

• And the alternative P450-dependent GSH conjugation pathway makeup remaining 5%.

When “ACETAMINOPHEN” Become Toxic?

• High therapeutic dose of “ACETAMINOPHEN” leads to saturation of Glucuronidation & Sulfation pathways.

• The P450- dependent pathway becomes more important.

• Here hepatic GSH i.e available for conjugation, can prevent from hepatotoxicity BUT…

Hepatic GSH can not regenerated as rapidly as it depleted.

• So, with time, its depletion occur.

• Thus, in the absence of hepatic GSH (IC nucleophiles), this reactive metabolite reacts with nucleophilic grps of cellular proteins

• w/h resulting in hepatotoxicity.

How To Overcome This Situation?

• Administration of N-acetylcysteine or Cysteamine within 8-16hours after overdosage of acetaminophen can protect victums from fulminant hepatotoxicity & death.

*Administration of GSH is not effective in this case b/c it does not cross cell membranes readily.

Clinical Relevance Of Drug Metabolism

• The dose & frequency of administration required to achieve effective therapeutic blood & tissue levels w/h vary in different patients due to INDIVIDUAL DIFFERENCES IN:

a. Drug Distribution.b. Rates of drug metabolism.c. Rates of drug elimination.

• These differences are determined by: 1. Genetic Factors: i. Hydrolysis of esters

ii. Acetylation of amines

2. Non Genetic Factors: i. Diet & environmental factors

ii. Age factors

iii. Drug-drug interaction factors: a. Enzyme inducing drugs b. Enzyme inhibiting drugs

Genetic Factors• There are several drug-metabolizing systems introduced to differ

among families or populations in genetically determined ways:

i. Hydrolysis of esters:

For Instance: SUCCINYLCHOLINE is an ester that is metabolized by plasma cholinesterase.

• In most individuals, this process occurs v. rapidly & a single dose of this neuromuscular blocking drug has a duration of action of about 5 MIN.

* App 1 persn in 2500 has an abnormal form of this enzyme that metabolizes “succinylcholine” & similar esters much more slowly.

• In such individuals, the neuromuscular paralysis produced by a single dose of succinylcholine may last many hours.

ii. Acetylation of amines:

• ISONIAZID & some other amines ( such as HYDRALAZINE & PROCAINAMIDE are metabolized by N-acetylation.

• Slow acetylators (individuals deficient in accetylation capacity), may have prolong or toxic responces to normal doses of these drugs.

* Slow acetylation triat is inherited as an autosomal recessive gene.

Non Genetic Factorsi. Diet & environmental factors:

• Diet & environmental factors contribute to individual variations in drug metabolism.DIET:• Charcoal-broiled foods & cruciferous vegetables are used to induce CYP1A enzymes.• Whereas grapefruit juice is used to inhibit CYP3A metabolism of coadministered

drug substrates.

ENVIRONMENTAL:• Industrial workers exposed to some pesticides, metabolize certain drugs more

rapidly than unexposed individuals.

ii. Age factors:• Inc. risk of pharmacologic or toxic action of

drugs has been seen in v. young & v. old patients as compared to the adult ones.

• This may be due to differences in absorption, distribution, elimination & drug metabolism.

• Slower metabolism could be due to reduced activity of metabolic enzymes.

iii. Drug-drug interaction factors:• Co-administration of certain agents may alter the disposition of

many drugs.

• Mech include the following:

a. Enzyme inducing drugs:• Induction usually results from inc. synthesis of cytochrome P450-

dependent drug-oxidizing enzymes, in the liver.

• Many isozymes of the P450 family already exist, & inducers just selectively inc. subgroups of isozymes.

• But several days are usually required to reach max. induction & a similar amount of time is required to regress after withdrawl of the inducer.

• The most common strong inducers of drug metabolism are CARBAMAZEPINE, PHENOBARBITAL & PHENYTOIN.

b. Enzyme inhibiting drugs:• The most common inhibitors of drug

metabolism involved in serious drug interactions are AMIODARONE, CIMETIDINE present in grapefruit juice.

• SUICIDE INHIBITORS are drugs that are metabolized by those products that irreversibly inhibit the metabolizing enzyme..

• Such as ETHINYL-ESTRADIOL, SECOBARBITAL etc.

THANK YOU!