On repeated administration drugs can induce CYP450 by enhancing the rate of its synthesis or reducing its rate of degradation but mainly in induction absolute increase in enzyme synthesis is seen. This induction leads to increase in rate of metabolite production, increased hepatic biotransformation, decrease in serum half life of drug, shorten drug response and could also lead to pharmacokinetic tolerance.
Xenobiotic influences the extent of drug metabolism by activating transcription and inducing the expression of genes encoding drug metabolism enzymes.
The mechanism of induction is incompletely understood but is similar to that involved in action of steroid that bind to nuclear receptors. Drugs bind to the ligand binding domain of a soluble protein, termed the aromatic hydrocarbon (Ah) receptor which is cytosolic in nature. This binding leads to conformational change in receptor which facilitates transportation of this complex to the nucleus by an Ah-receptor nuclear translocater and binds Ah-receptor response elements in the DNA thereby promoting transcription of the gene. For example, inducible expression of CYP3A is regulated by ligand-activated nuclear receptors CAR (constitutively active receptor) and can be activated by a wide variety of antibiotics, barbiturates etc. A similar kind of receptor mechanism invoving the pregnane X receptor (PXR) is also involved in the induction of CYP3A. In the case of CYP1A isoform, induction is through the binding of a ligand to Ah-receptor. Although CYP induction is normally the consequence of an increase in gene transcription, some non-transcriptional mechanisms also have been reported e.g., induction of human CYP2E 1
by ethanol and isoniazid is not transcriptional, but it results from protein stabilization or increased protein translation.
The onset and duration of induction depends both on the kinetics of the drug and half life of CYP enzyme, which ranges from 1-6 days.
Usually it takes 4-14 days for peak induction and on withdrawing inducer the CYP returns to their original level in 1-3 weeks.
Phenobarbital induce changes may be delayed for 14-22 days because of the long interval (long t 1/2
) before peak phenobarbital plasma levels are reached. In contrast, the onset of rifampicin induced increase in enzyme activity is only 4 days. 20-40 fold increase in enzyme activity is seen with phenobarbital whereas alcohol increase enzyme synthesis by 1-2 fold. Induction of CYP3A by rifampicin can lead to decrease in AUC of saquinavir by 80% and of ritonavir by 35%.
In addition to phenobarbital and rifampicin, glucocorticoids, macrolides, anticonvulsants induce specific forms of CYP3A. Isoniazid and chronic alcohol intake induce CYP2E1 which oxidizes ethanol and activates carcinogenic nitrosamine.
It must also be noted that an inducer may enhance not only the metabolism of other drugs but also its own metabolism. Thus, continued use of some drugs may result in a pharmacokinetic type of tolerance.
Important non pharmacological inducers include polycyclic aromatic hydrocarbons in cigarette smoke and charcoal broiled meat.
They causes induction of CYP1A2 and results in higher dosing requirements of drugs like theophylline in smokers. Other environmental chemical known to induce specific isoenzyme include polychlorinated biphenyls, which are used widely in industry as insulating materials and plasticizers. It has been observed that with age inducibilty of CYPs decreases.