Disease relevance of SR 1530

• The hypoxic radiosensitizers misonidazole or demethylmisonidazole were administered i.p. in a 2-liter volume to 6 patients affected by advanced ovarian carcinoma, and the pharmacokinetic course of the two drugs was studied [1].
• Desmethylmisonidazole was administered by continuous intraperitoneal infusion at a rate of 2.7 mg/gm body weight /24 hr [2].
• As part of a Phase I trial of hypoxic cell radiosensitizers, 19 women at Stanford University with advanced (n = 6) or recurrent (n = 13) pelvic neoplasms were treated with radiotherapy plus desmethylmisonidazole [3].
• 1. The hypoxic cell radiosensitizers misonidazole (RO 07-0582; Miso) and desmethylmisonidazole (RO 05-9963; Desmiso) were administered by the intraperitoneal route at a single dose of 250 mg/kg to Wistar rats bearing a chemo induced sarcoma [4].

High impact information on SR 1530

• The concentration x time exposure in the peritoneal fluid was 3.2 times larger than in plasma for misonidazole and 7.6 times for demethylmisonidazole [1].
• Pharmacokinetics of the hypoxic radiosensitizers misonidazole and demethylmisonidazole after intraperitoneal administration in humans [1].
• Evaluation of desmethylmisonidazole-induced neurotoxicity in the rat using brainstem auditory evoked potentials [5].
• Studies in mice showed that at a dose of 32 mg/kg given 30-60 min before, allopurinol had little or no effect on the clearance of misonidazole (MISO) or of the more lipophilic analogue Ro 07-0913, but did increase the blood concentrations of the hydrophilic dealkylation product desmethylmisonidazole (DEMIS) [6].
• Initial pharmacology and toxicology of intravenous desmethylmisonidazole [7].

Biological context of SR 1530

• Hydrophilic analogues, including desmethylmisonidazole, SR-2508, and SR-2555, were removed principally by renal clearance exhibiting linear elimination kinetics [8].
• The data were consistent with a model in which Miso is eliminated mainly after biotransformation into desmethylmisonidazole (Demiso) which is eliminated according to its renal clearance [9].

Anatomical context of SR 1530

• The concentration of desmethylmisonidazole in human tumours and in cerebrospinal fluid [10].
• Misonidazole (MISO) and desmethylmisonidazole (DMM) inhibit lactate production in CHO cells under aerobic conditions [11].
• Drug exposure to the peripheral nervous system was highest for misonidazole, followed by desmethylmisonidazole, etanidazole, pimonidazole and RK28 [12].
• The penetration of misonidazole and desmethylmisonidazole into brain tumours and other central nervous system tissues in man [13].
• The role of rat liver microsomes in the O-demethylation of misonidazole to desmethylmisonidazole was studied [14].

Gene context of SR 1530

• A further study with desmethylmisonidazole given to 11 additional patients showed a similar range of tumour penetration but lower concentrations in CSF and cyst fluid (10-20%) [13].

Analytical, diagnostic and therapeutic context of SR 1530

• These differences between the two routes of administration provide a rational basis for the expectation that a substantial increase of the therapeutic benefits of misonidazole and demethylmisonidazole in potentiating radiation therapy or chemotherapy can be expected in treating tumors confined to the i.p. space [1].
• Desmethylmisonidazole (Ro 05-9963): clinical pharmacokinetics after multiple oral administration [15].
• Radiosensitization of the RIF-1 murine flank tumor by desmethylmisonidazole (Ro 05 9963) during interstitial brachytherapy [2].
• We have investigated the interaction of the nitroimidazole radiosensitizer desmethylmisonidazole (Ro 05 9963) with interstitial radiation using a clonogenic cell assay as the endpoint [2].
• Simultaneous determination of misonidazole and desmethylmisonidazole in plasma by high-performance liquid chromatography [16].

References