Nicotinamide pharmacokinetics in humans and mice: a comparative assessment and the implications for radiotherapy

Horsman, Michael R.; Høyer, Morten; Honess, Davina J.; Dennis, Ian F.; Overgaard, Jens

doi:10.1016/0167-8140(93)90133-s

Cited by 82 publications

(73 citation statements)

References 34 publications

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“…In the absence of a specific carrier for nicotinamide, passage by passive diffusion across the hydrophobic cell membrane lining the gut wall would be expected to be slow. We, and other investigators (Stratford et al, 1992;Horsman et al, 1993) have shown that overnight fasting is effective in promoting rapid nicotinamide absorption. If this were a reflection of low gastric acid production, pharmacological suppression of its secretion with omeprazole would also improve the rate of uptake of nicotinamide.…”

Section: Discussionmentioning

confidence: 62%

“…Studies in both normal volunteers and in patients have shown wide variations in the time and magnitude of the peak concentration, and that these parameters can be modified by the type of drug formulation used (i.e. liquid vs tablet) and by food intake (Stratford et al, 1992;Horsman et al, 1993;Hoskin et al, 1995;Stratford et al, 1996). Overnight fasting and the use of a liquid formulation increase the uptake of nicotinamide and reduce variations between patients in the time to reach peak concentration.…”

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confidence: 99%

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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

Br J Cancer

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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.

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Section: Discussionmentioning

confidence: 62%

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

Br J Cancer

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“…The effective dose of NAM on blood flow is reported to be at concentrations from 100 mg kg-' and above (Chaplin et al, 1990). Horsman et al (1993 showed that there is no significant difference between the radiosensitising effect of NAM at doses of 100 mg kg-' and 1000 mg kg-1 in a C3H mammary carcinoma, even though the difference in plasma and tumour concentrations of NAM was 5-to 10-fold.…”

Section: Nad Pools In Tumour Tissuementioning

confidence: 99%

DNA damage and repair in tumour and non-tumour tissues of mice induced by nicotinamide

Olsson

Sheng²,

Pero³

et al. 1996

Br J Cancer

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Summary In vivo DNA damage and repair was induced by nicotinamide (NAM) in adenotype 12 virusinduced mouse sarcoma A12B3 and sarcoma F inoculated into CBA mice. DNA damage, NAM and NAD concentrations were measured after in vivo exposure to NAM, in tumours and spleens by alkaline elution and by HPLC analysis. Our results indicate that NAM between 100-1000 mg kg-' causes a high level of in vivo DNA strand breaks in tumours and normal tissues in mice bearing the immunogenic sarcoma A12B3 but not in the non-immunogenic sarcoma F. The repair process was also delayed by the NAM treatment probably owing to inhibition of the DNA repair enzyme, poly(ADP-ribose)polymerase, as evidenced by accumulation of NAM and NAD. These data are consistent with NAM having a mechanism of action as a radiosensitiser at least in part by DNA repair inhibition. In addition, it should also be considered that high doses of NAM might cause considerable complications to normal tissue in tumour-bearing individuals.

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“…in air without the drug, enhancement ratios in the order of 1.3-1.9 have been obtained for the combination of carbo gen and nicotinamide [3,12,14,15], Experimentally, plasma levels of 700 nmol/ml of nicotinamide are required at the time of irradiation to obtain a sensitising effect [8,15], Initial studies in healthy human volunteers showed that peak plasma levels of 800-1600 nmol/ml could be obtained after oral intake of 6 g [8,19]. Horsman et al showed that for maximal radiosensitization tumours should be inradiated at the time of peak drug levels [8].…”

Section: Introductionmentioning

confidence: 99%

“…Horsman et al showed that for maximal radiosensitization tumours should be inradiated at the time of peak drug levels [8].…”

Section: Introductionmentioning

confidence: 99%

Administration of nicotinamide during a five- to seven-week course of radiotherapy: pharmacokinetics, tolerance, and compliance

Kaanders

Stratford

Liefers

et al. 1997

Radiotherapy and Oncology

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Background and purpose: Nicotinamide was administered daily as a liquid formulation to head and neck cancer patients receiving a 5-to 7-week course of radiotherapy. The pharmacokinetics, compliance, and tolerance of this drug formulation were studied.Materials and methods: Blood samples were drawn and nicotinamide levels determined in 40 head and neck cancer patients. On the first treatment day serial samples were obtained followed by daily samples at the time of irradiation during the first and last full weeks of the treatment. Side-effects of nicotinamide were monitored.Results: In all patients peak concentrations greater than 700 nmol/ml could be obtained 0.25-3 h (mean 0.83 ± 0.73 h) after drug intake. During the first week of treatment plasma levels at the time of irradiation were adequate in 82% of the samples. This decreased to 59% in the last week of treatment which can be partly attributed to reduced compliance. The most important side-effect of nicotinamide was nausea with or without vomiting occurring in 65% of the patients. Severe side-effects were associated with high plasma concen trations over subsequent days. Tolerance improved after a 25% reduction of dose in six of seven patients but plasma levels at the time of irradiation fell below 700 nmol/ml in four out of six of these patients.Conclusions: Peak plasma concentrations above the 700 nmol/ml level were obtained in all patients but these concentrations could not be reproduced during the entire course of the treatment in a significant portion of the subjects. Side-effects of nicotinamide are associated with plasma concentrations and tolerance can be improved by a moderate reduction of dose.

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Nicotinamide pharmacokinetics in humans and mice: a comparative assessment and the implications for radiotherapy

Cited by 82 publications

References 34 publications

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

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

DNA damage and repair in tumour and non-tumour tissues of mice induced by nicotinamide

Administration of nicotinamide during a five- to seven-week course of radiotherapy: pharmacokinetics, tolerance, and compliance

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