INDUCTION, INHIBITION OF DRUG METABOLISM AND INHIBITION OF BILIARY EXCRETION


 

INDUCTION, INHIBITION OF DRUG METABOLISM AND INHIBITION OF BILIARY EXCRETION

Induction and Inhibition

  • Metabolism based drug-drug and other¢ interactions can have a significant influence on the use and safety of many drugs.
  • Induction of drug metabolism can lead to¢ unexpected drops in drug concentration or the build-up of metabolites.
  • The reverse can occur when there is inhibition of drug metabolism.
  • The major organ involved in metabolism is liver¢ and the major enzyme system involved in drug metabolism is CYP 450.

Induction

  •  The phenomenon of increased drug metabolizing ability of the enzymes by several drugs and chemicals is called as enzyme induction.
  •   A number of drugs can cause an increase in liver enzyme activity over time. This in turn can increase the metabolic rate of the same or other drugs.
  • Ex: phenobarbitone will induce the metabolism of itself, phenytoin, warfarin.
  • Dosing rates may need to be increased to maintain effective plasma concentrations.

Hormone induced CYP 450 expression:

  • Hormones induce induction of certain drugs like¢ tamoxifen, tacrine, acetaminophen and xenobiotics like dietary phytochemicals and carcinogens like aromatic amines produced in cooking and those found in cigarette smoke.

 Induction by inhibition interaction:

  • Insoniazid, ethanol and some xenobiotics induced CYP 2E1¢ and CYP3A1.
  • Well known example is induction of CYP2E1 by isoniazid and CYP3A1 by macrolide antibiotics.

Most Enzyme Inducers have following properties:

  • They are lipophilic compounds.
  • They are substrate for the induced enzyme system.
  • They have long elimination half lives.

Mechanisms involved in enzyme induction are:

  • Increase in both liver size and liver blood flow.
  • Increase in both total and microsomal protein content.
  • Increase in stability of enzymes.
  • Increase in synthesis of cytochrome P-450.
  • Proliferation of smooth endoplasmic reticulum.

Consequences of enzyme induction includes:

  • Decrease in pharmacological activity of drugs.
  • Increase in activity where the metabolites are active.
  • Altered physiological status due to enhanced metabolism of endogenous compounds such as sex hormones.

Inhibition

  • The phenomenon of decreased drug metabolizing¢ ability of the enzymes by several drugs and chemicals is called as enzyme inhibition.
  • The process of inhibition may be of two types:

Ø   [1]. Direct Inhibition  [2]. Indirect Inhibition

  • Direct Inhibition:- It may result from the interaction of enzyme site, the outcome being a change in enzyme activity.
  • Direct inhibition can occur by one of the three mechanisms:
  • Competitive inhibition:Eg: Methacholine inhibits metabolism of Ach by¢ competing with it for cholinesterase.
  • Non-competitive inhibition: Eg: Isoniazid inhibits the metabolism of Phenytoin¢ by the same enzymes.
  • Product Inhibition: Eg: Xanthine Oxidase inhibitors (Allopurinol) and¢ MAO inhibitors (Phenelzine) also inhibits the enzyme activity directly.
  • Indirect Inhibition;- It is brought about by one of the two mechanisms:

Ø  Repression: is defined as the decrease in¢ enzyme content.

Ø  Altered physiology: due to nutritional¢ defficiency or hormonal imbalance.

  • Enzyme inhibition is more important clinically than enzyme induction, especially for drugs with narrow therapeutic index, Eg: anticoagulants, antiepileptics, hypoglycemics.

Inhibition of Biliary Excretion

  • Drug interactions in biliary excretion:  Drugs or often conjugated and excreted in bile. Some drugs are excreted in bile biotransformation. Eg: In humans most water soluble drugs and metabolites of relatively high molecular weight are excreted largely in the bile.
  • This excretion is mainly via transporters and possibility exists for drug interaction with concomitant administration.
  • Hepatobiliary Drug Interaction: The co-administration of drugs which inhibits the co-transporter involved in biliary excretion can reduce the biliary excretion of drug , leading to elevated plasma drug concentration. Eg: Biliary and urinary of digoxin

Effect on biliary excretion:

  • Verapamil and cyclosporine are both inhibitors of p-gp, but through different mechanism, verapamil is a substrate for p-gp and is a competitive inhibitor of this pump, where as cyclosporine inhibit transport function by interfering with substrate recognition and ATP hydrolysis.
  • Decrease clearance of drug through inhibition of p-gp translates¢ clinically in to increased AUC and increased in toxicity. Examples:¢ * Decreased in vincristine clearance in presence of verapamil.

 

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