More than one potential source of induction of aripiprazole metabolism

A case report cum literature review published last year (I.R. McGrane and colleagues, Journal of Pharmacy Practice, 2017 January 1:897190017710523. doi: 10.1177/0897190017710523; published on the Web) corroborated a handful of earlier reported cases suggesting that aripiprazole bioavailability diminishes during coadministration of carbamazepine (attributed by authors of early reports to induction of CYP3A4 by carbamazepine).  The more recent report by McGrane and colleagues (op. cit.) described the first published case of diminished aripiprazole bioavailability in a patient during coadministration of oxcarbazepine (Trileptal), a chemical congener of carbamazepine that, like the latter, induces CYP3A4 (whose substrates include aripiprazole, which also has since been found to be a substrate of CYP2D6 and of CYP1A2).

The authors’ finding was predicated on a clinical finding of “lower than expected” aripiprazole blood concentrations in a child, and an in vitro assessment of oxcarbazepine-related increased expression of CYP3A4, from which they estimated that their patient’s aripiprazole blood concentration (for which there was no pre-oxcarbazepine baseline) represented a reduction of the latter by sixty-eight percent.

Indirectly assessed as it was, the potential effect of oxcarbazepine may apply to as many as 50 percent of drugs approved by FDA in the U.S. (the proportion comprising substrates of CYP3A4). Nevertheless, no mention is made of potential contributions of CYP1A2 and CYP2D6 (by dint of its high-activity phenotype of genetic origin (genetic duplication of the normal-activity allele, giving rise to ultra-rapid metabolism by CYP2D6)). Had baseline aripiprazole blood concentration been measured, it may have been lower than suspected because of rapid CYP2D6 metabolism; CYP3A4 induction may have been less robust than met the eye after a new equilibrium were established. The same kind of baseline skew might operate were the patient’s CYP1A2 induced by last night’s cauliflower or today’s cigarette smoking: the baseline aripiprazole concentration may be low for reasons having nothing to do with CYP3A4, which, when robustly induced may eventuate in a new aripiprazole baseline concentration interpreted as signifying less CYP3A4 induction than occurred. And so on: what could be the false positive from a poor metabolizer of CYP2D6 (because of the presence of two inactive alleles in their patient), with its higher baseline aripiprazole blood concentration, compared to its concentration after robust induction of CYP3A4? Or that associated with an abnormal allele of CYP3A4, with low activity and a higher baseline aripiprazole blood concentration? Having no baseline aripiprazole concentrations for comparison is tantamount to lacking a control sample, and speculating that the bioavailability of aripiprazole was reduced by 68 percent is an overreach, and nothing to justify an adjustment of aripiprazole dosing.

Aripiprazole hepatic metabolism is moderated by activities of cytochrome P450 enzymes other than CYP3A4 and its cross-sectional bioavailability at any given time will depend upon each of them and more (such as associated co-moderated activities of conjugation enzymes and membrane transport proteins that facilitate or block aripiprazole and aripiprazole metabolites’ passages through membranes in either direction).

Accordingly, careful empirical dosage adjustment with therapeutic monitoring remains the preferred approach to adjusting aripiprazole to safe and effective dosage after initiation or discontinuation of oxcarbazepine.  (Obiter: And induction of CYP2D6? The findings are few and mixed, pharmacologically (with potent corticosteroids having been reported to increase activity of CYP2D6,) Genetically, duplication of the normal CYP2D6 alleles is the most likely provenience of ultra-rapid CYP2D6 metabolism (unreported in the authors’ case). Among inducers of CYP3A4 other than oxcarbazepine are phenytoin, rifampin, carbamazepine, some of the HIV antiretroviral agents, St Johns wort, R-modafinil, and the R-modafinil/modafinil racemate. Another, more recently reported potential determinant of reduced aripiprazole bioavailability is CYP1A2, like CYPs 3A4 and 2D6, a phase I metabolic enzyme of aripiprazole. CYP1A2 is inducible by oxcarbazepine (I. Sugiyama and colleagues, Xenobiotica 46(9):765-774, 2016) as well as by polycyclic hydrocarbons of tobacco and marijuana smoke, the S-enantiomer of modafinil, and the alkaloids of cruciferous vegetables, such as broccoli, cauliflower, and brussels sprouts.) Writ large, the most valuable contribution of the authors’ case report cum review is its fostering of a realization that moderators of drug bioavailability are more complex than suspected in 2009, and in 2027 will likely prove more complex than we know them to be today.)

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