Effect of various cytochrome P450 3A and P-glycoprotein modulators on the biliary clearance of bromosulphaphthalein in male wistar rats.
The main aim of this study was to investigate the effect of various selective cytochrome P4503A (CYP3A) and/or P-glycoprotein (P-gp) modulators on biliary clearance of bromosulphaphthalein (BSP) in male albino wistar rats. Male albino wistar rats were divided into different groups, treated with CYP3A and P-gp modulators and BSP was administered intravenously (bolus or infusion) to each treated group. BSP in serum and bile samples was analyzed using spectrophotometric analysis at 580 nm. There was a statistically significant (p < 0.05) increase in serum BSP levels with CYP3A and P-gp substrates and/or inhibitors, cyclosporine-A, nitrendipine, quinidine, indinavir, daxorubicin, etoposide and erythromycin by 27%, 35%, 32%, 12%, 5%, 22%, and 106%, respectively. There was a slight increase (4%, p > 0.05) observed in serum BSP levels in the presence of ketoconazole, whereas CYP3A and P-gp inducers, rifampicin and sodium butyrate significantly (p < 0,05) decreased the serum BSP levels by 30% and 14% respectively, when compared to control group after 62 min of BSP i.v. bolus administration. In BSP infusion studies, Cyclosporine A, nitrendipine, quinidine, indinavir, ketoconazole, doxorubicin, etoposide, and erythromycin significantly decreased the bile BSP levels by 23%, 22%, 17%, 59%, 3%, 15%, 10%, 29%, respectively. Upon 60 min of BSP infusion, rifampicin and sodium butyrate significantly (p < 0.05) increased bile BSP levels by 33% and 25%, respectively. Finally, we observed that the P-gp and CYP3A inducers significantly decreased the total serum BSP levels and increased the total biliary levels of BSP, this could be by inducing P-gp in biliary canalicular membrane in male wistar rats. P-gp and CYP3A inhibitors and substrates significantly increased the total serum BSP levels and reduced the biliary excretion of BSP by inhibiting P-gp in biliary pathway. There was no significant difference observed between inhibitors and substrates of P-gp on BSP disposition. We suggest that the biliary transport of BSP could be useful as a simple and economical in vivo screening model for identifying P-gp and CYP3A substrates and/or inhibitors and/or inducers in wistar rats.
Machavaram
K K
KK
University College of Pharmaceutical Sciences, Kakatiya University, Warangal, Andhra Pradesh, India. machavaram_k@yahoo.com
Gundu
J
J
Yamsani
M R
MR
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D000818:Animals; D001646:Bile / Q000378:metabolism*; D002087:Butyrates / Q000494:pharmacology; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004317:Doxorubicin / Q000378:metabolism; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004917:Erythromycin / Q000494:pharmacology; D005047:Etoposide / Q000378:metabolism; D019469:Indinavir / Q000494:pharmacology; D007262:Infusions, Intravenous; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D007654:Ketoconazole / Q000494:pharmacology; D008297:Male; D009568:Nitrendipine / Q000494:pharmacology; D011802:Quinidine / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012293:Rifampin / Q000494:pharmacology; D013448:Sulfobromophthalein / Q000493:pharmacokinetics*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002087:Butyrates; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D013448:Sulfobromophthalein; D019469:Indinavir; D004917:Erythromycin; D005047:Etoposide; D004317:Doxorubicin; D003577:Cytochrome P-450 Enzyme System; D009568:Nitrendipine; D011802:Quinidine; D007654:Ketoconazole; D012293:Rifampin