Loss of enzyme induction: Ups and downs of a hidden drug-drug interaction

PGP is encoded on the same chromosome as CYP 3A4, and these 2 proteins frequently are expressed in the same cells, particularly in the intestinal lining and liver. Moreover, PGP is inducible, and there is substantial overlap between medications that are substrates for—or inducers of—PGP and CYP 3A4 activity. This makes it challenging to determine whether the kinetic effects of a second medication are the result of interference of 3A4, PGP, or both.

Polymorphisms in PGP activity may influence the penetration of psychotropic medications into the CNS. Studies indicate an association between certain PGP polymorphisms and treatment outcomes.^17,18

Table 1

What induces CYP 1A2 and 3A4?

Enzyme	Description	Inducers*
CYP 1A2	Responsible for 10% to 15% of all CYP P450 activity Located on chromosome 15 Low affinity/high capacity enzyme Low affinity/high capacity enzyme Prevalence of genetic polymorphisms conferring poor metabolizer status: 12% to 13%	Aryl hydrocarbons (smoking), protonpump inhibitors (omeprazole > lansoprazole > pantoprazole), modafinil, St. John’s wort, chargrilled meat, cruciferous vegetables such as broccoli and cabbage, flavones, protein supplements
CYP 3A4	Responsible for 30% of hepatic CYP 450 activity, 70% of gut cytochrome activity Located on chromosome 7 (same as PGP) Low affinity/high capacity enzyme Little evidence for significant functional polymorphisms	Carbamazepine, phenytoin, phenobarbital, rifampin, oxcarbazepine, efavirenz, glucocorticoids, modafinil, nevirapine, pioglitazone, St. John’s wort
* Listed in order from strongest to weakest induction
CYP: cytochrome P450; PGP: P-glycoprotein
Source: References 12,13

Stopping an inducer

In general, inducers of CYP enzymes stimulate gene transcription within hours of exposure; maximum transcriptional activity occurs after 10 to 12 hours of exposure. As transcription increases, the concentration of the CYP mRNA transcript steadily accumulates, as does concentration of CYP protein.

After an inducer is discontinued, transcription returns to basal levels within 18 hours; however, the degradation of CYP proteins is a first-order process, with a half-life of 8 to 30 hours. As a result, the decrease in cellular CYP concentration—and the level of activity—lags behind the decreased synthesis from reduced mRNA levels.

As with other first-order kinetic processes, the expected decrease in CYP activity will require 5 half-lives to reach the new steady state (ie, back to baseline CYP activity). This suggests that drug levels previously decreased by CYP induction will reach their peak on average 1 to 2 weeks after the inducer is discontinued.²⁰

Interactions with antipsychotics

Effects on serum antipsychotic levels caused by discontinuing a CYP or PGP inducer can be predicted from data on decreases in antipsychotic levels following inducer exposure. Except for ziprasidone and paliperidone, most atypical antipsychotics are prone to substantial decreases during concomitant inducer use (Table 2).²¹

The effect of enzyme inducers on risperidone is particularly interesting. Conversion of risperidone to its active metabolite 9-OH risperidone (paliperidone) occurs primarily via 2D6,²² yet concurrent use of carbamazepine—a potent CYP 3A4 inducer—results in a 50% decrease in the concentration of the active moiety (risperidone plus 9-OH risperidone). This finding and other early investigations suggested that CYP 3A had a role in risperidone metabolism,^23,24 but these early studies and case series often involved molecules that had activity at both 3A4 and PGP. Further research clarified that effects on PGP—and not 3A4—are responsible for the changes in risperidone metabolism observed with the use of carbamazepine and other medications.^25,26

Induction in case patients: Follow-up. Regardless of whether induction is mediated by ≥1 metabolic pathways, the loss of the inducer will result in serum antipsychotic increases that are proportional to the initial decrease.²⁰ For example, with risperidone, the expected decrease is 50%. Therefore, after Mr. P stopped taking phenytoin, his serum risperidone level would be expected to double, which resulted in extrapyramidal side effects.

Quetiapine clearance is increased 5-fold by inducer exposure, so a clinician treating Ms. K would expect a marked increase in somnolence—and possibly orthostasis—as serum quetiapine levels peak 1 to 2 weeks following carbamazepine discontinuation.

The effects of smoking cessation on serum clozapine levels have been well-documented.^1,27 Clinicians should anticipate median increases in serum clozapine levels of 55% after a patient discontinues smoking (aryl hydrocarbon exposure), but changes vary substantially among individuals. Mrs. T’s serum clozapine increased approximately 78%.

Careful clinical monitoring and slow downward adjustment of antipsychotic doses could have prevented the adverse effects these 3 patients experienced after loss of CYP/PGP induction and the consequences those side effects present for future medication adherence. When loss of induction is unplanned—as when Ms. K stopped taking carbamazepine but continued quetiapine—clinicians need to be alert to the fact that the patient was prescribed an inducer and include the loss of induction as a hypothesis for the patient’s somnolence.