An evaluation of para toluene-sulfonamide metabolism and effect with regard to CYP isoforms, P-glycoprotein, and drug interactions.
Aim of this study was to investigate liver metabolism of with regard to para toluene-sulfonamide (PTS), CYP isoforms, P-glycoprotein (P-gp), and drug interactions. Known substrates, inducers and inhibitors of CYP and inhibitor of P-gp were employed and metabolites were determined with HPLC. Male Wistar rats were pretreated with ip phenobarbital (PB), ketoconazole (Ket), or verapamil (Ver) for 3 days and in situ liver perfusion of PTS was conducted in a recirculation system. Rats were also pretreated with ip PTS (33 mg x kg(-1) x d(-1) or PTS 99 mg x kg(-1) x d(-1)) for 4 days before liver perfusions with dextromethorphan (Dex) and phenacetin (Phe) preparations were conducted. Microsome incubation was used to investigate PTS effect on five CYP isoforms and PTS-drug interactions probability with phyllotoxin and 5-fluorouracil (5-FU) in vitro. PTS at 60 min perfusates had areas of 61.4% and 133.6% of the blank control in PB group and Ket group, respectively. The result that PTS metabolism was enhanced by PB and inhibited by Ket treatments suggested liver CYP was attributed to PTS metabolism. PTS 99 mg x kg(-1) x d(-1) pretreatment slowed down the metabolism of Dex and Phe while in vitro incubations did not show a PTS (0-160 micromol/L) effect on CYP activities. PTS metabolite formation when co-incubated with phyllotoxin was 50.7% of the negative control. The potent inhibitory ability of phyllotoxin to PTS requires further clinical investigation regarding in concomitant administration.
Zhou
J Q
JQ
Department of Pharmacy, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, PR China. zhoujiangquan@gmail.com
Tang
Z Q
ZQ
Zhang
J N
JN
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002138:Calibration; D002851:Chromatography, High Pressure Liquid; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004347:Drug Interactions; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000378:metabolism; D007649:Ketamine / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D010424:Pentobarbital / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D015203:Reproducibility of Results; D013449:Sulfonamides / Q000378:metabolism*; D014050:Toluene / Q000031:analogs & derivatives* / Q000378:metabolism; D014700:Verapamil / Q000494:pharmacology; D000096926:Benzenesulfonamides
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002121:Calcium Channel Blockers; D003577:Cytochrome P-450 Enzyme System; D018691:Excitatory Amino Acid Antagonists; D007527:Isoenzymes; D007649:Ketamine; D010424:Pentobarbital; D013449:Sulfonamides; D014050:Toluene; D014700:Verapamil; C025417:4-toluenesulfonamide; D000096926:Benzenesulfonamides