Overlapping functions of ABC transporters in topotecan disposition as determined in gene knockout mouse models

It is established that efflux transporters of the ATP-binding cassette (ABC) superfamily can affect the pharmacokinetics of drugs through mechanisms pertaining to drug absorption, elimination, and distribution. To characterize the role of multiple transporters in topotecan's pharmacokinetics, total (lactone+carboxylate) and lactone forms were measured by liquid chromatography/tandem mass spectrometry (LC/MS-MS) in plasma, bile, urine, and feces following intravenous administration at doses of 1 and 4 mg/kg to eight mouse strains: C57BL/6 [wild-type (WT)], Abcb1(-/-), Abcc2(-/-), Abcc4(-/-), Abcg2(-/-), Abcc2;Abcb1(-/-), Abcc2;Abcg2(-/-), and Abcc4;Abcg2(-/-). Compared with WT mice and at both dose levels, the plasma areas under the curve for topotecan lactone were not significantly different in the Abcc2(-/-), Abcc4(-/-), and Abcb1(-/-) strains, whereas significant differences were found in Abcg2(-/-), Abcc2;Abcb1(-/-) (only at the high dose), Abcc4;Abcg2(-/-), and Abcc2;Abcg2(-/-) mice and ranged from 2.1- to 3.3-fold higher. Consistent with these changes, the fecal and biliary excretion of topotecan was reduced, whereas renal elimination was elevated in Abcg2(-/-)-based strains. Similarly, the Abcc2;Abcb1(-/-) strain also had elevated renal elimination and reduced fecal excretion of topotecan lactone. This was more pronounced at the 4 mg/kg dose level, suggesting possible saturation of Abcg2. The Abcc4 transporter was found not to be a major determinant of topotecan pharmacokinetics. It is concluded that Abcg2 has the most significant effect on topotecan elimination, whereas both Abcb1 and Abcc2 have overlapping functions with Abcg2. As such it is relevant to examine how polymorphisms in these transporters influence topotecan activity in patients and whether coadministration of transport modulators could positively affect efficacy without increasing toxicity.