Studies on the cellular pharmacology of N-(4-methylphenylsulfonyl)-N′-(4-chlorophenyl)-urea

Glutathione and Mercapturic Acid Conjugates of Sulofenur and Their Activity against a Human Colon Cancer Cell Line

“…These observations were consistent with the inhibitory properties of their corresponding glutathione conjugate analogs derived from the substituted ureas discussed earlier Guan et al, 1994Guan et al, , 1999Jochheim and Baillie, 1994). Furthermore, our study has revealed that both conjugates exhibited inhibitory activity comparable to the parent drug against the human colon adenocarcinoma GC 3 /c1 cell line, a cell line that has been widely employed to explore the anticancer mechanism(s) of sulofenur and other anticancer diarylsulfonylureas (Houghton et al, 1990(Houghton et al, , 1995Sosinski et al, 1991Sosinski et al, , 1993Rush et al, 1992;Phelps et al, 1995).…”

“…The objectives of this study were to determine whether GS-C(O)-NH-R (R ϭ p-chlorophenyl) is a metabolite of sulofenur, whether the conjugate is a GR inhibitor, and further, whether the conjugate exhibits cell growth-inhibitory activity by using human colon adenocarcinoma GC 3 /c1 cells, a sulofenur-sensitive cell line. The GC 3 /c1 cell line has been widely employed to explore the anticancer mechanisms of sulofenur and other anticancer diarylsulfonylureas (Houghton et al, 1990(Houghton et al, , 1995Sosinski et al, 1991Sosinski et al, , 1993Rush et al, 1992;Phelps et al, 1995). In addition, a glutathione conjugate can be enzymatically converted to a mercapturic acid conjugate (Williams, 1995).…”

Imatinib Mesylate Is a Potent Inhibitor of the ABCG2 (BCRP) Transporter and Reverses Resistance to Topotecan and SN-38 in Vitro

“…After attachment overnight at 37°C, medium was aspirated, and cells were washed twice with 2 ml of physiological Tris buffer [20 mM Tris containing 120 mM NaCl, 3 mM K 2 HPO 4 , 0.5 mM MgCl 2 , 1 mM CaCl 2 , and 10 mM glucose (pH 7.4)]. Monolayers were incubated at room temperature in physiological Tris for 10 min before aspiration of buffer and replacement with 1 ml of serum-free RPMI 1640-HEPES buffer containing 0.5 Ci/ml [ 14 C]imatinib mesylate (specific activity, 91.5 Ci/mg; final concentration, 1 M) with or without 10 mM NaN 3 (9). After the appropriate period of incubation at room temperature (5 min), medium was rapidly aspirated to terminate drug accumulation and replaced with drug-free medium for efflux studies.…”

Pharmacokinetics of the Anticancer Agent Sulofenur in Mice, Rats, Monkeys, and Dogs

“…In the rodents, tmax is reached after [4][5][6][7][8] h. In dogs and in monkeys, absorption appears to be even slower, with t,, values of 12 and 24 h, respectively. Thus, it is not surprising that absorption of sulofenur apparently does not occur in the stomach, but only in the intestinal tract, which has been confirmed in rats.22 This may be due to the insolubility of sulofenur (pK, = 5.5; K, is the association constant) in acidic media.…”

“…Separations were achieved with a 5 x 250-mm Synchrome Synchropak SCD-100 with 3 x 10-mm guard column (Synchropak SCD-100 packing) along with a saturation column (4 x 20 mm, Synchropak SCD-100 packing) placed between the pump and autoinjector. The LC gradient program involved initial elution with 10% acetonitrile10.025 M pH 6.5 NaP04 at 1.0 mWmin with linear change to 20% acetonitrile from 0-6 min, linear change to 35% acetonitrile from [8][9][10][11][12][13][14][15][16][17][18] min, and linear change to 50% acetonitrile from 23-29 min, where sulofenur, metabolites 2 and 3, and internal standard LY186642 had retention times of 25. 8, 15.6, 18.8, and 26.8 min, respectively. Separated plasma fractions were thawed and 25 pg of internal standard LY186642 was added to 0.3 mL of each sample.…”