Metabolism and effect of para-toluene-sulfonamide on rat liver microsomal cytochrome P450 from in vivo and in vitro studies.
OBJECTIVE
To study the in vivo and in vitro metabolism and the effect of para-toluene-sulfonamide (PTS) on cytochrome P450 enzymes (CYP450).


METHODS
Total CYP450 and microsome protein content were determined after iv pretreatment of rats with PTS. CYP-specific substrates were incubated with rat liver microsomes. Specific CYP isoform activities were determined by using HPLC. CYP chemical inhibitors added to the incubation mixture were used to investigate the principal CYP isoforms involved in PTS metabolism. The effect of PTS on CYP isoforms was investigated by incubating PTS with specific substrates.


RESULTS
The groups treated with 33 and 99 mg/kg per d PTS, respectively, had a total CYP content of 0.66+/-0.17 and 0.60+/-0.12 nmol/mg. The K(m) and V(max) were 92.2 micromol/L and 0.0137 nmol/min per mg protein. CYP2C7, CYP2D1 and CYP3A2 might contribute to PTS metabolism in the rat liver. The inhibitory effects of sulfaphenazole and ketoconazole on PTS metabolism were shown to have a mixed mechanism, whereas PTS metabolism was inhibited noncompetitively by quinidine. PTS had little effect on the activities of the selected CYP isoforms.


CONCLUSIONS
Generally speaking, it is relatively safe for PTS to be co-administered with other drugs. However, care should be taken when administering PTS with CYP inhibitors and the substrates of CYP2C, CYP2D and CYP3A.
Zhou
Jiang-Quan
JQ
Department of Pharmacy, Cancer Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100021, China. zhoujiangquan@gmail.com
Tang
Zhi-Qiang
ZQ
Zhang
Jin-Nan
JN
Tang
Jing-Cheng
JC
D000429:Alcohol Oxidoreductases / Q000378:metabolism; D000818:Animals; D000890:Anti-Infective Agents / Q000494:pharmacology; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D000072467:Cytochrome P450 Family 2; D007654:Ketoconazole / Q000494:pharmacology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D013379:Substrate Specificity; D013426:Sulfaphenazole / Q000494:pharmacology; D013449:Sulfonamides / Q000378:metabolism* / Q000494:pharmacology; D014050:Toluene / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D000096926:Benzenesulfonamides
D000429:Alcohol Oxidoreductases; D000890:Anti-Infective Agents; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System; D000072467:Cytochrome P450 Family 2; D007654:Ketoconazole; D008565:Membrane Proteins; D013426:Sulfaphenazole; D013449:Sulfonamides; D014050:Toluene; C493085:Cyp2c7 protein, rat; C504568:Cyp2d1 protein, rat; C465260:Cyp3a2 protein, rat; C025417:4-toluenesulfonamide; D000096926:Benzenesulfonamides