In vivo and in vitro antitumor effects of ILX651, a pentapeptide with anovel mechanism of action.

2122 There is considerable interest in the development of COX-2 (cyclooxygenase-2) and HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase inhibitors as potential chemopreventive agents. Several in vitro and in vivo studies have shown that celecoxib (COX-2 inhibitor) and lovastatin (HMG-CoA reductase inhibitor) are promising candidates for chemoprevention and/or adjuvant chemotherapy. The current study was performed to investigate the in vitro metabolism of celecoxib and lovastatin when used as single agents or in combination. In addition, the potential for interactions with other concomitant drugs was investigated by evaluating the effect of celecoxib and lovastatin on standard probe substrate assays. Incubation and HPLC assay conditions were optimized for the formation and quantitation of the major metabolites of celecoxib (hydroxy celecoxib) and lovastatin (6′β-hydroxy lovastatin) in human liver microsomes. The formation of hydroxy celecoxib and 6′β-hydroxy lovastatin by human liver microsomes best fit to the Hill equation, with Km values of 10 and 31 μM, respectively. A screen of 19 individual cDNA expressed CYP isoforms (CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP3A4, CYP3A5, CYP3A7, CYP4A11, CYP4F2, CYP4F3A, CYP4F3B, and CYP 19) indicated that CYP2C9, CYP2D6 and CYP1A1 were predominantly responsible for celecoxib hydroxylation and CYP3A4, CYP3A5 and CYP3A7 played a significant role in lovastatin metabolism. Co-incubation of celecoxib and lovastatin in human liver microsomes resulted in inhibition of the metabolism of each drug at high concentrations. Lovastatin inhibited the formation of hydroxy celecoxib in a concentration-dependent manner at three different concentrations (3, 7.5 and 15 μM) of celecoxib, with a mean IC 50 ∼ 100 μM. Celecoxib was capable of inhibiting the formation of 6′s-hydroxy lovastatin at three concentrations (25, 50 and 75 μM) of lovastatin with a mean IC 50 ∼ 100 μM. Evaluation of the effect of celecoxib on the metabolism of probe substrates of CYP2C9 (diclofenac), CYP2D6 (bufuralol), CYP1A1 (7-ethoxy resorufin) and CYP3A4 (testosterone) indicated a significant inhibitory effect of celecoxib on diclofenac (IC 50 ∼ 10 μM) and bufuralol (IC 50 ∼ 2 μM) hydroxylation. Celecoxib did not affect CYP3A4 and CYP1A1 activities. Lovastatin significantly inhibited testosterone hydroxylation, with an average IC 50 ∼ 25 μM. These results indicate that celecoxib can potentially interfere with the metabolism of concomitantly administered drugs or dietary components that are CYP2C9 and CYP2D6 substrates. Similar interaction can be expected between lovastatin and CYP3A4 substrates. Supported by NCI Contract N01-CN-35126.