Pharmacokinetic and Metabolic Studies of the Hypoxic Cell Radiosensitizer Misonidazole

Summary.-I.p. administration at several dose levels over periods of up to 12 weeks, or continuous i.v. infusion of high doses of misonidazole (MISO) for 15 h, produced no significant change in peripheral nerve conduction velocity (NCV) and did not prevent the normal increase in NCV as the animals matured from 12 to 24 weeks of age. Peripheral NCV (sural nerve) was reduced in both MISO-treated and control mice with hind-limb tumour implants, presumably owing to physical pressure due to tumour growth. In addition, neither the medial nerves nor the tibial nerve in the normal limbs of the tumour-implanted, drug-treated animals showed any change. Consequently our earlier and present studies do not confirm the recent reports of changes in NCV following either acute or chronic MISO administration to mice.

Section: Discussionsupporting

confidence: 93%

Effect of acute and chronic misonidazole administration on peripheral-nerve electrophysiology in mice

Conroy¹,

Burg²,

Penney³

et al. 1980

“…The difference in concentration between digested and undigested whole blood gave the amount of glucuronidase-hydrolysable conjugates of MIS and Ro-05-9963. In accordance with previous convention (Flockhart et al, 1978c) (Flockhart et al, 1978b;Stone, personal communication, 1978). For both drugs the deaths of the animals were rapid: even at doses close to the LD50 only an occasional mouse died beyond 5-6 h after injection.…”

Section: Methodsmentioning

confidence: 81%

“…Thus, a valid direction in drug design would be to decrease the halflife without losing the high plasma and tumour levels achievable with MIS. Since the half-life in man is -12 h (Foster et al, 1975;Dische et al, 1977;Wiltshire et al, 1978;Workman et al, 1978b) (Reidenberg, 1974(Reidenberg, , 1977. Kidney ligation also precludes any metabolism of the drugs by the kidney.…”

Section: Discussionmentioning

confidence: 99%

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Pharmacokinetic considerations in testing hypoxic cell radiosensitizers in mouse tumours

Brown¹,

Yu²,

Workman³

1979

Summary.-Bilateral kidney ligation of mice immediately before injection of misonidazole (MIS) prolongs the plasma half-life of this radiosensitizer from about 2 h (in normal mice) to 10-11 h, similar to that in man. Kidney ligation does not, however, change the relative proportions of MIS and its 0-demethylated metabolite, , for the first 12 h after MIS injection. Kidney ligation was used with the two radiosensitizers, MIS and Ro-05-9963, to investigate the influence of plasma half-life both on peak plasma levels and on the tumour/plasma ratio of sensitizer concentration in the EMT6 mouse tumour.Although the acute LD50 of Ro-05-9963 in normal mice was twice that of MIS. this apparent advantage was offset by peak tumour levels 5000 or less of those achieved by equimolar injected doses of MIS. However, by comparing the plasma and tumour levels in mice in which the drug half-lives were prolonged by bilateral kidney ligation, it was concluded that the lower plasma and tumour levels of Ro-05-9963 were a result of its shorter plasma half-life, rather than of an intrinsic barrier to tumour penetration. Because of this rapid clearance, the radiosensitization produced by Ro-05-9963 was less than that produced by equimolar injected doses of MIS. As this difference did not occur in kidney-ligated mice, and hence would not be expected to occur in man, the comparison of MIS and Ro-05-9963 in mice produces an artificially low radiosensitization for Ro-05-9963 and possibly also for other compounds with short plasma half-lives.Although the short plasma half-life of Ro-05-9963 appeared to be responsible for its low peak plasma concentration, it did not produce a low tumour/plasma ratio. Within the limits of plasma nitroimidazole half-lives investigated (0-5-10 h) the tumour/plasma ratio was insensitive to plasma half-life, being 50-70% for both MIS and Ro-05-9963 in both normal and kidney-ligated mice. It is concluded that the common assumption that tumour/plasma ratios of MIS in the mouse are less than those in man is unjustified.

“…Despite major contributions to our understanding of MISO metabolism (Stratford & Adams, 1978;Chin et al, 1980;Varghese et al, 1976) we are still unsure of the nature of the reactive product(s) which binds to the macromolecules and of the reducing enzymes (Flockhart et al, 1978;McManus et al, 1982;Rauth, 1984;Franko, 1986).…”

mentioning

confidence: 99%

NAD(P)H nitroblue tetrazolium reductase levels in apparently normoxic tissues: a histochemical study correlating enzyme activity with binding of radiolabelled misonidazole

Cobb¹,

Hacker²,

Nolan³

1990

Hack and Helmy's method for the histochemical identification of NAD(P)H nitroblue tetrazolium reductase activity was employed to pinpoint reductase activity in certain cells in the mouse. High activity was observed in the following: lower airway epithelium, liver (centrilobular zone), eyelid (meibomian and sebaceous glands), vulval gland and parotid gland (striated cells of intralobular ducts). All of these cells had previously been identified as sites of binding of the reactive metabolites formed from the enzymic reduction of misonidazole (MISO) (Cobb et al., 1989). It had previously been thought that MISO binding would only take place in significant amounts in hypoxic tissues (tumour and possibly liver) since in normoxic tissues oxygen should reverse the initial one electron enzymic reduction, thus preventing progressive reduction to reactive species. We suggest that the very high levels of reductase in the above listed, probably normoxic, tissues contribute significantly to the accumulation of bound reactive MISO metabolite(s). Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7