CYP2C75-Involved Autoinduction of Metabolism in Rhesus Monkeys of Methyl 3-Chloro-3′-fluoro-4′-{(1R)-1-[({1-[(trifluoroacetyl)amino]cyclopropyl}carbonyl)amino]ethyl}-1,1′-biphenyl-2-carboxylate (MK-0686), a Bradykinin B₁ Receptor Antagonist

Abstract

After oral treatment (once daily) for 4 weeks with the potent bradykinin B 1 receptor antagonist methyl 3-chloro-3Ј-fluoro-4Ј-{(1R)-1-[({1-[(trifluoroacetyl)amino]cyclopropyl}carbonyl)-amino]ethyl}-1,1Ј-biphenyl-2-carboxylate (MK-0686), rhesus monkeys (Macaca mulatta) exhibited significantly reduced systemic exposure of the compound in a dose-dependent manner, suggesting an occurrence of autoinduction of MK-0686 metabolism. This possibility is supported by two observations. 1) MK-0686 was primarily eliminated via biotransformation in rhesus monkeys, with oxidation on the chlorophenyl ring as one of the major metabolic pathways. This reaction led to appreciable formation of a dihydrodiol (M11) and a hydroxyl (M13) product in rhesus liver microsomes supplemented with NADPH. 2) The formation rate of these two metabolites determined in liver microsomes from MK-0686-treated groups was Ն2-fold greater than the value for a control group. Studies with recombinant rhesus P450s and monoclonal antibodies against human P450 enzymes suggested that CYP2C75 played an important role in the formation of M11 and M13. The induction of this enzyme by MK-0686 was further confirmed by a concentration-dependent increase of its mRNA in rhesus hepatocytes, and, more convincingly, the enhanced CYP2C proteins and catalytic activities toward CYP2C75 probe substrates in liver microsomes from MK-0686-treated animals. Furthermore, a good correlation was observed between the rates of M11 and M13 formation and hydroxylase activities toward probe substrates determined in a panel of liver microsomal preparations from control and MK-0686-treated animals. Therefore, MK-0686, both a substrate and inducer for CYP2C75, caused autoinduction of its own metabolism in rhesus monkeys by increasing the expression of this enzyme.Cytochromes P450 (P450s) are a superfamily of enzymes involved in the oxidative metabolism of a variety of chemical xenobiotics, including pharmaceuticals, carcinogens, and environmental pollutants (Wrighton and Stevens, 1992). Altered catalytic activity or capacity of the enzymes, by inhibition or induction, is the major source of metabolism-based drug-drug interactions (Tanaka, 1998). The past decades have witnessed the advance in prediction of drug-drug interactions due to P450 inhibition (Brown et al., 2006), but pre-

Use of In Vivo Animal Models to Assess Pharmacokinetic Drug-Drug Interactions

“…The following case investigated in our lab (65) exemplifies the divergent outcome of auto-induction in rhesus monkeys and humans, and the mechanic investigation of the event. A potent bradykinin B 1 receptor antagonist was primarily eliminated via biotransformation in rhesus monkeys, with oxidation on the chlorophenyl ring as one of the major metabolic pathways.…”

Macaque cytochromes P450: nomenclature, transcript, gene, genomic structure, and function

“…Of these, African green monkey CYP2C9 has been characterized. African green monkey CYP2C9 is involved in diclofenac 4′ -and 5-hydroxylation (Table 3), but much less than either human CYP2C9 or rhesus CYP2C19 (Tang et al, 2008). Marmoset CYP2C8 cDNA is 93% identical to human CYP2C8 cDNA (Table 2), and its protein metabolizes tolbutamide (Table 3), but not diclofenac, S-mephenytoin, or paclitaxel (Narimatsu et al, 2006).…”

Neuropeptides: Metabolism to Bioactive Fragments and the Pharmacology of Their Receptors

“…Human PK data from MK-0686 are available. 391 Interestingly, it has recently been reported that B 1 receptor antagonists, such as LF22-0542 (44), a water-soluble arylsulfonamide are promising candidates for treating diabetic retinopathy after ocular application. 392 Common binding motifs of aryl sulfonamides and biarylmethyl amines have been proposed 393 and all data from structureactivity relationship and homology modeling 394,395 should hopefully promote the discovery of investigational drugs antagonizing the B 1 receptor and that are successful in clinical use.…”