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.

Modifications to the previously reported spiroindenylpiperidine camphor-sulfonamide oxytocin (OT) antagonist L-366,509 have produced a new series of o-tolylpiperazine (TP) camphor-sulfonamides. A number of analogues in the TP series that incorporate a modified or unmodified L-methionine sulfone amide at the C2 endo position on the camphor ring exhibit high affinity for OT receptors (IC50 = 1.3-15 nM) and good selectivity for binding to OT versus arginine vasopressin V1a and V2 receptors. Several of these analogues were additionally characterized as potent antagonists of OT-stimulated contractions of the isolated and/or in situ rat uterus. Compound 7 (L-368,899) exhibited the best overall profile of OT receptor affinity (IC50 = 8.9 nM, rat uterus; 26 nM, human uterus), potency for inhibition of OT-stimulated contractions of the isolated rat uterus (pA2 = 8.9) and in situ rat uterus (AD50 = 0.35 mg/kg after intravenous (i.v.) administration and 7.0 mg/kg after intraduodenal administration), aqueous solubility (3.7 mg/mL at pH 5.0), and oral bioavailability in several species (35% (rat), 25% (dog), and 21% (chimpanzee) as estimated from radioreceptor determination of drug levels in plasma after oral and i.v. dosing). On the basis of these favorable properties, 7 has begun clinical testing for use as an oral and i.v. tocolytic agent. Molecular modeling alignment studies have provided support for the hypothesis that the TP camphor-sulfonamide portion of the non-peptide structures may serve as a mimetic of the important D-AA2-Ile3 dipeptide (AA = aromatic amino acid) found in many potent OT antagonists from the cyclic hexapeptide and OT analogue structural classes.

Biotransformation studies performed on an investigational compound (I, represented by R1-CH(NH(2))-CO-N(R2)-CH(2)-S-R3) led to the identification of five metabolites (M1-M5). Based on LC/MS (liquid chromatography/mass spectrometry) analysis which included the use of H(2)O and D(2)O in the mobile phases, they were identified as the sulfoxide (M1), sulfone (M2), carbamoyl glucuronide (M3), N-glucuronide (M4), and N-glucoside (M5) metabolites, respectively. The structure of M3, a less commonly seen carbamoyl glucuronide metabolite, was established using on-line H/D (hydrogen/deuterium) exchange experiments conducted by LC/MS. H/D exchange experiments were also used to distinguish the S-oxidation structures of M1 and M2 from hydroxylation. Herein, the application of deuterium oxide as the LC/MS mobile phase for structural elucidation of drug metabolites in biological matrices is demonstrated.

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