Studies on the cellular pharmacology of N-(4-methylphenylsulfonyl)-N'-(4-chlorophenyl)-urea.
The cellular pharmacology of N-(4-methylphenylsulfonyl)-N'-(4-chlorophenyl)-urea (MPCU) has been examined in a cloned line of GC3 human colon adenocarcinoma cells. There was a rapid concentrative accumulation of drug, which could be separated into energy-independent and -dependent phases. Accumulation over 15 sec was linear and temperature dependent, but not energy dependent (azide insensitive). The rate of uptake was a linear function of concentration over a wide range (0.0026 to 5 mM). No saturation kinetics were demonstrated. Steady state was achieved within 10 min, and drug levels associated with GC3/C1 cells exceeded the extracellular concentration by 4- to 6-fold. This second phase "concentrative accumulation" of drug was azide sensitive. When cells were incubated to steady state in the presence of azide, removal of azide (with addition of glucose) resulted in a further uptake of sulfonylurea to a higher steady state. When [3H]MPCU was removed from the medium after achieving steady state, loss of drug from cells was rapid (T1/2 approximately 130 sec), and no tight-binding component was apparent. After achieving steady state, cell-associated drug was lost into drug-containing medium reaching a lower steady state if 10 mM azide (+/- glucose) was added. These data indicate that MPCU may enter cells by a non-saturable energy-independent process (passive diffusion) and bind weakly to some intracellular component or become sequestered to some compartment in an energy-dependent manner.
Houghton
P J
PJ
Department of Biochemical and Clinical Pharmacology, St. Jude Children's Research Hospital, Memphis, TN 38101.
Bailey
F C
FC
Germain
G S
GS
Grindey
G B
GB
Howbert
J J
JJ
Houghton
J A
JA
D000230:Adenocarcinoma / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000378:metabolism*; D001386:Azides / Q000494:pharmacology; D002021:Buffers; D002460:Cell Line; D003110:Colonic Neoplasms / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D010042:Ouabain / Q000494:pharmacology; D019810:Sodium Azide; D013453:Sulfonylurea Compounds / Q000378:metabolism*
D000970:Antineoplastic Agents; D001386:Azides; D002021:Buffers; D013453:Sulfonylurea Compounds; C062821:LY 181984; D010042:Ouabain; D019810:Sodium Azide