Monitoring salivary misonidazole in man: a possible alternative to plasma monitoring

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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.

Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Pharmacokinetic considerations in testing hypoxic cell radiosensitizers in mouse tumours

Brown¹,

Yu²,

Workman³

1979

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“…The method is invasive, inconvenient to patients and nursing staff and expensive as it requires skilled manpower to obtain the sample. The use of saliva as a diagnostic fluid in pharmacokinetic studies and in particular in therapeutic drug monitoring is very well established (Mandel, 1993), and has been previously suggested for use in clinical trials with radiosensitisers (Workman et al, 1978). Therefore, we have developed a method for determining nicotinamide levels in saliva and have compared these profiles with those obtained in plasma.…”

mentioning

confidence: 99%

Nicotinamide pharmacokinetics in humans: effect of gastric acid inhibition, comparison of rectal vs oral administration and the use of saliva for drug monitoring

Stratford

Dennis²,

Hoskin³

et al. 1996

Summary The effect of inhibiting gastric acid secretion on nicotinamide pharmacokinetics was studied in five volunteers with the intent of reducing the large variations observed previously in the time to and magnitude of peak plasma concentrations. Plasma levels were determined using a standard high-performance liquid chromatography (HPLC) method after an oral dose of 3 g of nicotinamide either alone or preceded by pretreatment with omeprazole. Suppression of gastric acid production had no significant effect on the rate of uptake or on the peak levels achieved. To bypass gastric acidity, the rectal route was also assessed using a suppository in four volunteers and one patient undergoing radiotherapy. Absorption was slow and variable and much lower plasma levels were observed than after oral dosing. Thus, no improvement in the pharmacokinetics of nicotinamide was observed using either of these two approaches. Parallel estimations were made using a novel and non-invasive method for monitoring nicotinamide pharmacokinetics in saliva. A large and variable fraction of the total amount of nicotinamide-related material in saliva was found to be nicotinic acid, a metabolite not normally found in human plasma. This conversion was inhibited by the use of a chlorhexidine mouthwash, indicating that the oral flora was responsible for its production. The time to peak levels of nicotinamide or of nicotinamide plus nicotinic acid in saliva correlated well with that in plasma. However, peak concentrations for nicotinamide alone were significantly lower than in plasma, and very variable, whereas for nicotinamide plus nicotinic acid saliva levels were 20-30% higher, but more consistent. Although there are some practical difficulties in quantitatively handling saliva, the method is very useful for monitoring nicotinamide pharmacokinetics and for assessment of compliance with nicotinamide treatment.

“…In addition, pretreatment with these agents significantly reduces the acute lethal effects of MISO in mice (Workman, 1980 Blood samples were taken by venipuncture immediately before MISO administration and at various times after, usually 2, 1, 2, 4, 8, 12, 24 and 30 h. Plasma concentrations of MISO and DEMIS were determined by reverse-phase high-performance liquid chromatography (HPLC) (Workman et al, 1978a). Pharmacokinetic parameters were calculated as described previously (Workman et al, 1978b;Workman, 1979). Statistical analysis was by Student's t test.…”

mentioning

confidence: 99%

Phenytoin shortens the half-life of the hypoxic cell radiosensitizer misonidazole in man: implications for possible reduced toxicity

Workman¹,

Bleehen²,

Wiltshire³

1980

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Previous studies from this laboratory have shown that pretreatment with phenytoin or phenobarbitone shortens the halflife of MISO in mice and dogs through induction of hepatic drug-metabolizing enzymes, which increase the rate of oxidative demethylation of MISO to desmethylmisonidazole (1-(2-nitroimidazol-1 -yl)-2,3-propandiol; Ro 05-9963, Roche Laboratories; NSC 261036; DEMIS) (Workman, 1979; White & Workman, 1979). In addition, pretreatment with these agents significantly reduces the acute lethal effects of MISO in mice (Workman, 1980 Blood samples were taken by venipuncture immediately before MISO administration and at various times after, usually 2, 1, 2, 4, 8, 12, 24 and 30 h. Plasma concentrations of MISO and DEMIS were determined by reverse-phase high-performance liquid chromatography (HPLC) (Workman et al., 1978a). Pharmacokinetic parameters were calculated as described previously (Workman et al., 1978b;Workman, 1979). Statistical analysis was by Student's t test.The pertinent pharmacokinetic data are summarized in Table I. Comparison of the data obtained on the first MISO dose revealed no significant differences between the control and phenytoin groups for any of the kinetic parameters (P> 0 1). This indicated that the pharmacokinetics of MISO were initially very similar for the two groups.For the control group, comparison of the data for the first and second doses of MISO showed that the percentage change for