caa a22 4500 477127266 CHVBK 20180405111653.0 cr unu---uuuuu 170330e19971001xx s 000 0 eng 10.1023/A:1012189225880 doi (NATIONALLICENCE)springer-10.1023/A:1012189225880 The Pharmacokinetics of Topotecan and Its Carboxylate Form Following Separate Intravenous Administration to the Dog [Elektronische Daten] [Brian Davies, Elisabeth Minthorn, Michael Dennis, Hilde Rosing, Jos Beijnen] Purpose. To determine the relationship between topotecan and its ring opened hydrolysis product (SK&F 105992) following intravenous administration of the two agents separately, and to determine the bio-availability of topotecan in female beagle dogs. Methods. The pharmacokinetics of topotecan and SK&F 105992 were determined following separate administration as 30 minute intravenous infusions in a cross-over design. Topotecan was also administered orally to the same dogs. Results. When administered intravenously to dogs, SK&F 105992 underwent interconversion to topotecan. Plasma concentrations of both topotecan and SK&F 105992 appeared to decline multi-exponentially following IV infusion of either compound. A 2-compartment model was found to adequately characterize the data. Conclusions. The clearance of topotecan by other routes proceeded at a faster rate than its interconversion to SK&F 105992, whereas the clearance of SK&F 105992 by other routes was slower than the rate of its interconversion to topotecan. Any SK&F 105992 formed in the GI tract did not appear to be well absorbed following oral administration of topotecan to dogs. The steady-state volume of distribution for topotecan was approximately 8- to 9-fold greater than that for SK&F 105992 in the dog. After intravenous administration of topotecan, the amount of topotecan in the dog was much greater than that of the carboxylate, even though their respective plasma concentrations were similar. The bioavailability of topotecan, calculated from oral topotecan data or from SK&F 105992 data, was approximately 50%. Plenum Publishing Corporation, 1997 topotecan nationallicence pharmacokinetics nationallicence topoisomerase I inhibitor nationallicence reversible metabolism nationallicence Davies Brian Department of Pharmacokinetics, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania aut Minthorn Elisabeth Department of Pharmacokinetics, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania aut Dennis Michael Department of Pharmacokinetics, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania aut Rosing Hilde Department of Pharmacokinetics, Bracco Diagnostics, Princeton, New Jersey aut Beijnen Jos Department of Pharmacokinetics, Bracco Diagnostics, Princeton, New Jersey aut Pharmaceutical Research Kluwer Academic Publishers-Plenum Publishers 14/10(1997-10-01), 1461-1465 0724-8741 14:10<1461 1997 14 11095 https://doi.org/10.1023/A:1012189225880 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1023/A:1012189225880 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Davies Brian Department of Pharmacokinetics, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania aut NATIONALLICENCE 700 1- Minthorn Elisabeth Department of Pharmacokinetics, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania aut NATIONALLICENCE 700 1- Dennis Michael Department of Pharmacokinetics, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania aut NATIONALLICENCE 700 1- Rosing Hilde Department of Pharmacokinetics, Bracco Diagnostics, Princeton, New Jersey aut NATIONALLICENCE 700 1- Beijnen Jos Department of Pharmacokinetics, Bracco Diagnostics, Princeton, New Jersey aut NATIONALLICENCE 773 0- Pharmaceutical Research Kluwer Academic Publishers-Plenum Publishers 14/10(1997-10-01), 1461-1465 0724-8741 14:10<1461 1997 14 11095 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer