Pharmacokinetics of four different brands of colistimethate and formed colistin in rats

Objectives: Very different labelling conventions are employed by different products of colistimethate (CMS), an inactive prodrug of colistin that is used as a last-line defence against Gram-negative 'superbugs'. This study examined the chemical composition and pharmacokinetics in rats of four commercial parenteral products of CMS. Methods: Contents per vial of four brands of CMS from three different continents were weighed (n = 3). Elemental analysis and HPLC examination were conducted. The pharmacokinetics of CMS and formed colistin were investigated for each product after intravenous administration in rats (28.1 mg/kg CMS; n = 4). Blood was collected over 180 min, and concentrations of CMS and colistin were measured followed by pharmacokinetic analysis. Results: X-GEN, Paddock and Atlantic products, labelled with 150 mg 'colistin base activity', contained 366.8 +/- 0.80, 340.6 +/- 0.08 and 380.0 +/- 5.97 mg CMS (sodium) per vial, respectively; while the Forest product (labelled with 2000000 IU) contained 159.3 +/- 1.75 mg CMS (sodium). The elemental compositions of the four products were similar; however, the HPLC profile of the Atlantic CMS was different from those of the other three products. The pharmacokinetics of CMS were generally comparable across brands; however, the molar ratios (%) of the AUC(0-180min) of colistin to CMS (1.68%+/- 0.35% to 3.29%+/- 0.43%) were significantly different (P = 0.0157). Conclusion: This is the first study to demonstrate that although different brands of CMS from various parts of the world have similar elemental compositions, they lead to different exposures to the microbiologically active formed colistin. The study has significant implications for the interpretation of pharmacological studies of CMS conducted in different parts of the world.