Effect of Cyclosporine on Colchicine Secretion by A Liver Canalicular Transporter Studied In Vivo

Abstract

The multidrug resistance transport protein is a normal constituent of the liver canalicular membrane, although its function has not been defined in vivo. Colchicine, a multidrug resistance substrate, is eliminated mainly by the liver. Cyclosporine reverses multidrug resistance in vitro, presumably by inhibiting the multidrug resistance transporter. This study assesses biliary colchicine elimination and the effect of cyclosporine on this process. After cyclosporine administration biliary colchicine clearance decreased from 11.6 +/- 0.8 to 2.2 +/- 0.4 ml/min.kg (p less than 0.05), and the colchicine bile/plasma ratio decreased from 166 +/- 9 to 38 +/- 5 (p less than 0.05). Cremophor EL (a cyclosporine vehicle) transiently inhibited biliary colchicine clearance and colchicine bile/plasma ratio, but to a much smaller extent than cyclosporine in vehicle. Biliary cyclosporine clearance was 0.122 and 0.024 ml/min.kg after bolus doses of 2 or 10 mg/kg intravenously, respectively. Cyclosporine bile/plasma ratio was 1.3 to 5.2. When cyclosporine was given 16 hr before colchicine infusion, biliary colchicine clearance decreased 39% (p less than 0.05), and colchicine bile/plasma ratio decreased 51% (p less than 0.05). Thus colchicine is actively secreted into bile and will be useful in the study of the multidrug transporter in vivo. Cyclosporine profoundly inhibits colchicine secretion into bile but is itself mainly metabolized rather than secreted. If competition for a common carrier is the basis for the interaction, then cyclosporine represents a drug that binds to but is not transported by the canalicular transporter.

Multiple Efflux Pumps Are Involved in the Transepithelial Transport of Colchicine: Combined Effect of P-Glycoprotein and Multidrug Resistance-Associated Protein 2 Leads to Decreased Intestinal Absorption Throughout the Entire Small Intestine

“…Although the focus of this work is the intestinal absorption process after oral administration, our data may be relevant to other colchicine pharmacokinetic processes, e.g., distribution and clearance. Indeed, decreased colchicine biliary clearance from 0.122 to 0.024 ml/min/kg by cyclosporine through P-gp inhibition has been reported (Speeg et al, 1992), leading to increased colchicine plasma levels, and to a clinically relevant interaction. Because MRP2 is expressed on the canalicular membrane and plays an important role in the biliary excretion of various drugs, the fact that colchicine is a MRP2 substrate as revealed in this article may point out new mechanism-based drug-drug interactions.…”

Colchicine-induced toxicity in a heart transplant patient with chronic renal failure

“…First, cyclosporine inhibits P-glycoprotein resulting in increased intracellular colchicine concentrations and decreased hepatic and renal excretion of the drug (13). Second, cyclosporine interacts with CYP3A4 (14) to decreases the hepatic elimination of colchicine (15).…”

Organic Isothiocyanates: Dietary Modulators of Doxorubicin Resistance in Breast Cancer

“…In the kidney, P-gp is highly expressed on the brush border of the proximal renal tubule. Speeg et al have demonstrated the inhibition of renal clearance of colchicine by cyclosporin, suggesting that MDR modulators may alter the renal elimination processes of anticancer drugs by blocking P-gp in kidneys [30]. P-gp and some isoforms of MRP are present in the apical membrane of intestinal epithelial cells, where they can -limit the absorption of xenobiotics, and in the canalicular membrane of hepatocytes where they can affect biliary excretion.…”

“…10 pg/ml for 1-NITC, 1-NA, and 1-NIC; 50 pg/ml for NE). The stability ofl-NITC, 1-NA, and 1-NIC in universal buffer was carried on, in a broad pH range from 2 to 12 a. RT (with data points a, 0, 2,4,8,16,24,30,36,48,60,72,84, and 96 h) with same concentration as in nlasmn Th* J ■ m plasma. The compound is considered stable if the variation of quantitation is less than 10% (i.e.…”