Abstract
We have investigated the effects of 50 min whole-body hyperthermia (WBH; 15 min equilibration followed by 41 degrees C for 35 min) on the toxicity and pharmacokinetics of the radiosensitizer Ro 03-8799 in mice. WBH markedly reduced Ro 03-8799 LD50/7d from 779 to 259 micrograms g-1 (P less than 0.001). Pharmacokinetics were studied at 175 micrograms g-1 (approximately 0.6 WBH LD50/7d) with and without heat and 437 micrograms g-1 (approximately 0.6 control LD50/7d) without heat. WBH increased Ro 03-8799 plasma concentrations and prolonged its elimination t1/2 by 26% (P less than 0.01). Total plasma area under the curve (AUC0-infinity) was increased by 22%, but was still less than 50% of the unheated high-dose value. Ro 03-8799 concentrated 300-400% in tumour and brain relative to plasma. Absolute tumour and brain levels were unaltered by WBH, giving reduced tissue/plasma ratios. WBH greatly inhibited glomerular filtration (51Cr EDTA clearance) during heating, contributing to the increased plasma Ro 03-8799 concentrations. WBH increased peak plasma concentrations of the Ro 03-8799 N-oxide metabolite Ro 31-0313 by 61% and the beta-phase AUC of i.v. administered Ro 31-0313 by 36%. Since Ro 31-0313 levels were increased to a greater extent after Ro 03-8799 and WBH than Ro 31-0313 and WBH, WBH must both increase metabolite production and decrease its plasma clearance. WBH had no effect on Ro 31-0313 tumour concentrations or its exclusion from brain. These complex effects of WBH on Ro 03-8799 pharmacokinetics may contribute to the enhanced toxicity, possibly through hyperthermia-stimulated bioreductive drug activation, but do not wholly explain it.
Highlights
We have examined the effects of whole-body hyperthermia (WBH) on the toxicity and pharmacokinetics of Ro 03-8799 in mouse
Since Ro 03-8799 is eliminated by both metabolic and renal clearance (Walton et al, 1985) we investigated the effects of WBH on glomerular filtration rate (GFR) using 51Cr EDTA (Chantler et al, 1969)
We show that WBH has a complex effect on Ro 03-8799 pharmacokinetics
Summary
Adult C3H/He mice were obtained from our own breeding colony and from Olac Ltd (Bicester, UK). Males were used in most experiments but females were used occasionally. Mice were allowed food (PRD nuts; Labsure, Poole, Dorset, UK) and water ad lib, and were used at 25-35 g body weight. The KHT sarcoma was grown in the gastrocnemius muscle of the hind leg as previously described (Twentyman et al, 1979). Mice were treated bearing tumours in the size range 0.4-0.8g
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