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Vol. 26, Issue 4, 360-366, April 1998
Department of Biopharmaceutical Sciences, School of Pharmacy,
University of California, San Francisco
K02 (morpholine-urea-Phe-Hphe-vinylsulfone), a newly developed
peptidomimetic, acts as a potent cysteine protease inhibitor, especially of cathepsins B and L (which are associated with cancer progression) and cruzain (a cysteine protease of Trypanosoma
cruzi, which is responsible for Chagas' disease).
Here we investigated features of the disposition of K02 using in
vitro systems, characterizing the interaction of the drug with
human cytochrome P450 (CYP) 3A and P-glycoprotein (P-gp), a mediator of
multidrug resistance (MDR) to cancer chemotherapy and a
countertransporter in the intestine that limits oral drug
bioavailability. P-gp functions as an ATP-dependent drug efflux pump to
reduce intracellular cytotoxic concentrations. An HPLC assay was
developed to analyze K02 and its metabolites formed in human liver
microsomes. Three major primary metabolites were determined by LC/MS/MS
to be hydroxylated products of the parent compound. A rabbit anti-CYP3A
polyclonal antibody (200 µl antibody/mg microsomal protein) produced
75-94% inhibition of the formation of these three hydroxylated
metabolites. Ketoconazole (5 µM), a selective CYP3A inhibitor,
produced up to 75% inhibition, whereas other CYP-specific inhibitors,
i.e. quinidine (CYP2D6), 7,8-benzoflavone (CYP1A2), and
sulfaphenazole (CYP2C9), showed no significant effects. An identical
metabolite formation profile for K02 was observed with cDNA-expressed
human CYP3A4 (Gentest). These data demonstrate that K02 is a substrate
for CYP3A. Formation of 1'-hydroxymidazolam, the primary human
midazolam metabolite, was markedly inhibited by K02 via
competitive processes, which suggests the potential for drug-drug
interactions of K02 with other CYP3A substrates. K02 significantly
inhibited the photoaffinity labeling of P-gp with azidopine and
LU-49888, a photoaffinity analogue of verapamil. Transport studies with
[14C]K02, using MDR1-transfected
Madin-Darby canine kidney cell monolayers in the Transwell system,
demonstrated that the basolateral-to-apical flux of K02 across
MDR1-transfected Madin-Darby canine kidney cells was
markedly greater than the apical-to-basolateral flux (ratio of 63 with
10 µM [14C]K02). This suggests that K02 is
also a P-gp substrate. These studies are important for formulating
strategies to increase the absorption and/or decrease the elimination
of K02 and to optimize its delivery to malignant cells and
parasite-infected host cells.
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