Cytochrome P450 3a4 Is the Major Enzyme Involved in the Metabolism of the Substance P Receptor Antagonist Aprepitant

Abstract

ABSTRACT:The contribution of human cytochrome P450 (P450) isoforms to the metabolism of aprepitant in humans was investigated using recombinant P450s and inhibition studies. In addition, aprepitant was evaluated as an inhibitor of human P450s. Metabolism of aprepitant by microsomes prepared from baculovirus-expressed human P450s was observed only when CYP1A2, CYP2C19, or CYP3A4 was present in the expression system. Incubation with CYP1A2 and CYP2C19 yielded only products of O-dealkylation, whereas (Navari et al., 1999;Campos et al., 2001). A dosing regimen of aprepitant consists of a combination therapy with a 5-hydroxytryptamine 3 receptor antagonist, such as ondansetron, and a corticosteroid (e.g., dexamethasone, methylprednisolone) (Roila et al., 1998;Gralla et al., 1999). Thus, the use of this novel drug presents a potential for interactions with chemotherapeutic agents as well as adjuvant therapies.In drug-drug interaction studies, it was observed that coadministration with aprepitant resulted in increases in the area under the plasma concentration versus time curve (AUC) for dexamethasone and methylprednisolone . When the standard dexamethasone regimen (20 mg on day 1 and 12 mg on days 2-5) was given concomitantly with aprepitant, dexamethasone AUC 0 -24 h increased ϳ2-fold on both day 1 and day 5 compared with the standard dexamethasone regimen alone. When a modified dexamethasone regimen (12 mg on day 1 and 4 mg on days 2 and 5) was given concomitantly with aprepitant, the dexamethasone AUC 0 -24 h also increased, making it similar to that of the standard regimen alone. When 125 mg of methylprednisolone i.v. on day 1 and 40 mg p.o. on days 2 and 3 was given with aprepitant, the AUC of methylprednisolone increased approximately 30% on day 1 (after i.v. administration) and 2-fold on day 3 (after oral administration). Aprepitant had no effect on either ondansetron (i.v.) or granisetron (p.o.) pharmacokinetics (Blum et al., 2003). Dexamethasone, methylprednisolone, and granisetron are metabolized by CYP3A4 (Glynn et al., 1986;Bloomer et al., 1994;Gentile et al., 1996;Varis et al., 1998), whereas ondansetron is metabolized by multiple P450 isoforms, including CYP1A2, CYP2D6, and CYP3A4 (Fischer et al., 1994;Dixon et al., 1995).Furthermore, clinical drug interaction studies indicated that administration of aprepitant at two different dosing regimens for 5 days altered the pharmacokinetics of the CYP3A4 probe substrate midazolam, when administered on days 1 and 5 of aprepitant therapy. The pharmacokinetic changes included 2.3-and 1.5-fold increases in midazolam AUC and maximum observed plasma concentration, respectively . Collectively, these results suggested that aprepitant is a moderate inhibitor of CYP3A4.

Drug–Drug Interaction Studies: Regulatory Guidance and An Industry Perspective

“…The observed temporal changes in the aprepitant exposure (increase on day7 then decrease on day28), but not of midazolam, suggest a possibility for changes over time in the relative contribution of CYP3A to overall metabolism of aprepitant that was not replicated with midazolam. Although the underlying mechanism remains to be investigated, this hypothesis is consistent with the fact that aprepitant is also metabolized, albeit to a very limited extent by CYP2C in vitro, is not a potent inhibitor of CYP2C (86), and that an inducer of CYP3A can also induce CYP2C (87,88). This example highlights a knowledge gap requiring more targeted studies to better understand the underlying mechanisms for the observed unpredictable time-dependent outcome, which could be incorporated into a more refined PBPK model that better captures all potential contributing factors.…”

Interindividual Variations in Aprepitant Plasma Pharmacokinetics in Cancer Patients Receiving Cisplatin-Based Chemotherapy for the First Time

“…11,12) Although bilirubin is one of the hepatic functional markers for liver injury, the T-Bil value of all study patients was within the normal reference range. These results indicate that the influence of T-Bil on the pharmacokinetics of aprepitant may be remarkable, because T-Bil affected the plasma exposure of aprepitant despite the normal reference range.…”

“…11,12) CYP1A2 and CYP2C19 yielded only products of O-dealkylation, whereas CYP3A4 catalyzed both N-and O-dealkylation reactions. The products derived from the N-dealkylation and subsequent reactions were eliminated in feces, while the products of Odealkylation were eliminated in urine.…”

“…12) Aprepitant is metabolized to seven metabolites, which have lower binding affinities for the NK 1 receptor and lower plasma concentrations. Therefore, aprepitant is more responsible for the antiemetic activity 7,13) and adverse effects than that of its metabolites.…”

Controlling Chemotherapy-Induced Nausea and Vomiting with Neurokinin-1 Receptor Antagonists in Patients on AC-Based Chemotherapy—Are We There Yet?

“…As CR comprises both parameters of "no vomiting" and "no rescue medication use", this may have contributed to the equivocal CR rates between arms. Since aprepitant is both a substrate and moderate inhibitor of CYP3A4 [29,30], genetic differences [29,31] may have accounted for the varying aprepitant efficacies between this study, which comprised of 100% ethnic Chinese patients, and similar studies which sampled a large proportion of Caucasians [22].…”