A new method for the measurement of nitrosoureas in plasma: an h.p.l.c. procedure for the measurement of fotemustine kinetics.
1. An analytical method for a novel nitrosourea, fotemustine, has been developed using solid-phase extraction and h.p.l.c. with u.v. detection. As part of the development, different methods for stabilising fotemustine after sample collection have been investigated. The method has been successfully applied to pharmacokinetic studies in monkeys and man. 2. Providing plasma was separated immediately from blood and frozen within 3 min of collection, negligible degradation of fotemustine occurred. The samples could then be stored at -20 degrees C in the dark for up to six days particularly if thawing prior to analysis was accelerated using a 50 degrees C water-bath so that it was complete within 3 min. Equivalent results were also obtained with samples stabilised with 0.1 M citric acid immediately after the preparation of plasma. 3. The analytical method showed good precision with a within-day variation ranging between +/- 10.7% at the lowest concentration investigated (0.1 micrograms ml-1) to 2.0% at 50.0 micrograms ml-1. The accuracy of measurement was from 108.9% to 97.6% at 0.1 and 50.0 micrograms ml-1 respectively and the response was linear up to 50 micrograms ml-1. The minimum level of quantitation was 20 ng ml-1. 4. After a single intravenous bolus dose of [14C]fotemustine (100 mg m-2) to Cynomolgus monkeys, intact drug levels rapidly declined (t1/2 12.6 +/- 0.5 min) although the half-life of radioactivity (approx 100 h) was much longer. The plasma clearance of fotemustine was 225 +/- 63 ml min-1 with a volume of distribution based on area of 4.1 +/- 1.2 litres. 5. As with monkey, plasma levels of intact fotemustine in a patient given [14C]-drug as a 1 h constant rate intravenous infusion (approx. 100 mg m-2), declined rapidly but with a half-life of 23.2 min. Again, the half-life for total radioactivity was considerably longer (30.8 h). The plasma clearance was 1426 ml min-1 and the volume of distribution based on area was 47.71.
Gordon
B H
BH
Servier Research and Development Ltd., Fulmer Hall, Slough, UK.
Richards
R P
RP
Hiley
M P
MP
Gray
A J
AJ
Ings
R M
RM
Campbell
D B
DB
D000818:Animals; D002250:Carbon Radioisotopes; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D006207:Half-Life; D006801:Humans; D009607:Nitrosourea Compounds / Q000097:blood / Q000493:pharmacokinetics; D009943:Organophosphorus Compounds / Q000097:blood / Q000493:pharmacokinetics; D011865:Radioisotope Dilution Technique
D002250:Carbon Radioisotopes; D009607:Nitrosourea Compounds; D009943:Organophosphorus Compounds; C054368:fotemustine