Impact of Solutol HS 15 on the pharmacokinetic behaviour of colchicine upon intravenous administration to male Wistar rats.
In the current investigation, the alkaloid colchicine was administered intravenously to male Wistar rats both as a solution in isotonic sodium chloride (NaCl 0.9%, control group) and in NaCl 0.9%:Solutol HS 15 (95:5) at 1.5 mg/kg. At predetermined time points, plasma and urine were collected from the animals and analysed for colchicine and its demethylated metabolites by LC/MS-MS. In the presence of Solutol HS 15, colchicine clearance (CI) was significantly decreased and its maximum plasma concentration (c(max)) was significantly increased as compared to the control group (CI: 15.6+/-7.0 ml/min/kg vs 34.3+/-2.3 ml/min/kg; c(max) 3055.1+/-587.4 h vs 1260.1+/-223.7 h; p<0.05). Moreover, the amount of parent colchicine excreted into urine was markedly increased in the Solutol HS 15 treated group (41.50+/-3.23 vs 1.17+/-0.41% of total dose; p<0.05). By contrast, there was no statistically significant difference but a trend to lower values only in the volume of distribution (V(d) 13.3+/-2.2 l/h vs 31.4+/-17.7 l/h, p=0.35). The half-lives for the first (t(1/2 1stphase). 0.21+/-0.02 h vs 0.20+/-0.03 h) and second phase (t(1/2 2ndphase). 18.5+/-6.9 h vs 18.3+/-7.7 h) did not differ significantly in dependence on the dosing vehicle. The free fraction in rat plasma (FF), the blood/plasma (lambda) and erythrocyte/plasma concentration ratios (K(e)) were not significantly changed in the presence of different concentrations of Solutol HS 15 compared with surfactant-free incubations (overall means: 72.25+/-0.50% for FF, 0.80+/-0.02 for lambda, 0.46+/-0.04 for K(e)). In vitro, in rat hepatocytes, the clearance of colchicine was significantly reduced at 0.003% Solutol HS 15 present in the incubation medium (0.86+/-0.15 microl/min/10(-6) cells vs 1.46+/-0.06 microl/min/10(-6) cells). As colchicine exhibits a comparatively high aqueous solubility, an impact of Solutol HS 15 on the solubility of the alkaloid is very unlikely to be a reason for the observed effect. Therefore, our results indicate that the most likely reasons for the changed pharmacokinetic behaviour of colchicine in the presence of Solutol HS 15 are alterations of metabolism and/or transport as well as distribution and elimination processes.
Bittner
Beate
B
Discovery DMPK, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, Basel, Switzerland. beate.bittner@roche.com
González
Roberto Carlos Bravo
RC
Walter
Isabelle
I
Kapps
Martin
M
Huwyler
Jörg
J
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D003078:Colchicine / Q000008:administration & dosage* / Q000378:metabolism / Q000493:pharmacokinetics*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005079:Excipients / Q000378:metabolism / Q000493:pharmacokinetics; D022781:Hepatocytes / Q000737:chemistry / Q000187:drug effects; D007275:Injections, Intravenous; D008297:Male; D011092:Polyethylene Glycols / Q000009:adverse effects / Q000378:metabolism / Q000493:pharmacokinetics*; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D013229:Stearic Acids / Q000009:adverse effects / Q000378:metabolism / Q000493:pharmacokinetics*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D005079:Excipients; D013229:Stearic Acids; D011092:Polyethylene Glycols; C067028:Solutol HS 15; D003577:Cytochrome P-450 Enzyme System; D003078:Colchicine