Pharmacokinetics and whole-body distribution of the new chemotherapeutic agent beta-D-glucosylisophosphoramide mustard and its effects on the incorporation of [methyl-3H]-thymidine in various tissues of the rat.
beta-D-Glucosylisophosphoramide mustard (beta-D-Glc-IPM) is a new, potential chemotherapeutic agent currently under investigation. Its pharmacokinetics in plasma and elimination of the parent drug and its metabolites via urine, bile, and exhaled air were studied in female Sprague-Dawley rats after bolus injection of 315 mg/kg. Typically, the drug's disposition from plasma follows a linear two-compartment model with half-lives (t1/2) of 1.8 (t1/2 alpha) and 32 min (t1/2 beta). The rate of clearance is 0.0046 (range 0.0030-0.0071) 1 min-1 kg-1, and the steady-state volume of distribution (Vss) is 0.18 (0.08-0.042) 1/kg (mean +/- inter-individual standard deviation). In human plasma, 28.1 +/- 2.6% (mean +/- SD) of the drug (concentration range 0.5-5 mg/ml) is bound to plasma proteins (predominantly to albumin). Biliary excretion of the parent drug accounts for 2.9 +/- 1.7% of the dose; its elimination in the form of 14CO2 via exhaled air is less than 1%. Within 24 h, 63.5 +/- 4.9% of the 14C-labeled drug is excreted unchanged in the urine, whereas 17.5 +/- 5.1% is excreted in the urine as metabolites. In addition, beta-D-Glc-[14C]-IPM was given as a bolus injection to female Sprague-Dawley rats at dose levels of 315 and 56.2 mg/kg. The distribution of radioactivity into tissue was examined qualitatively by whole-body autoradiography (WBA). Parallel experiments were carried out using the high dose of the L-derivative. After dosing with the D-compound, the highest levels of radioactivity were found in the liver, kidneys, thymus, thyroid gland, and central nervous system, including the brain. A similar distribution pattern was observed for the L-compound, except in the brain, which contained negligible levels of radioactivity. The distribution of the D-compound (high dose) was also investigated in male Copenhagen rats bearing a Dunning prostate tumor. The results were similar to those obtained in healthy Sprague-Dawley rats. Additionally, radioactivity was found in the tumor at 1 h after dosing with the drug and remained there even after 24 h. The effects of beta-D-Glc-IPM on the incorporation of [methyl-3H]-thymidine into the DNA of the liver, kidneys, thymus, spleen, esophagus, and bone marrow of the rat were examined following tissue excision and liquid scintillation counting at 2, 8, and 24 h after administration of the drug. beta-D-Glc-IPM showed no effect on the incorporation of [methyl-3H]-thymidine in the liver and an insignificant reduction in kidney DNA (maximal reduction: -27.3%). However, after 8 h there was a marked reduction in the incorporation rate in the thymus (-83.7%), spleen (-74.6%), and esophagus (-87.2%), with a tendency toward recovery within 24 h. In bone marrow cells a reduction of -75.5% (8 h) and -73.3% (24 h) was observed.
Stüben
J
J
Division of Molecular Toxicology, German Cancer Research Center, Heidelberg, Germany.
Port
R
R
Bertram
B
B
Bollow
U
U
Hull
W E
WE
Schaper
M
M
Pohl
J
J
Wiessler
M
M
D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000493:pharmacokinetics*; D001345:Autoradiography; D001646:Bile / Q000378:metabolism; D004273:DNA, Neoplasm / Q000378:metabolism; D005260:Female; D005947:Glucose / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics; D006207:Half-Life; D006801:Humans; D007069:Ifosfamide / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics; D008297:Male; D008657:Metabolic Clearance Rate; D011471:Prostatic Neoplasms / Q000378:metabolism; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D012709:Serum Albumin / Q000378:metabolism; D013237:Stereoisomerism; D013936:Thymidine / Q000031:analogs & derivatives* / Q000378:metabolism; D014018:Tissue Distribution; D014316:Tritium
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D012709:Serum Albumin; C092028:beta-D-glucosylisophosphoramide mustard; D014316:Tritium; C012439:methylthymidine; D005947:Glucose; D007069:Ifosfamide; D013936:Thymidine