Pharmacokinetics of nicotinamide and its effect on blood pressure, pulse and body temperature in normal human volunteers

Stratford, Michael R.L.; Rojas, Ana M.; Hall, D.W.; Dennis, Madeleine F.; Dische, Stanley; Joiner, Michael C.; Hodgkiss, R.J.

doi:10.1016/0167-8140(92)90193-x

Cited by 65 publications

(38 citation statements)

References 16 publications

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“…Following doses of 4-6g in tablet formation (51-108mgkg-') the magnitude of peak concentration and plasma clearance were consistent with previous findings on normal volunteers (Stratford et al, 1992;Horsman et al, 1993a) and were both dose dependent. The time to reach peak plasma concentration was widely variable and was independent of dose, as in Stratford's study using the same formulation, but unlike Horsman's results using a capsule formulation, after which the time to reach peak concentration occurred predictably within 45 min of ingestion.…”

Section: Dimsciosupporting

confidence: 77%

“…Although it has been previously used with little toxicity in daily doses of up to 12 g in the treatment of benign disease (Zackheim, 1981), its use in patients with neoplastic disease is novel. Its pharmacokinetics has been measured in man at doses up to 6 g (Stratford et al, 1992;Horsman et al, 1993a), but its optimum dose, formulation and timing of administration in relation to radiation treatment are not yet fully established. Early studies suggested that radiosensitisation in murine tumour models occurs only at doses which would-be toxic in man (Brown, 1992), but a recent study has suggested that enhancement is independent of dose provided that radiation is given when nicotinamide plasma concentration is at its peak (Horsman et al, 1993a) and that doses of 6 g in man should be enough to produce tumour sensitisation.…”

mentioning

confidence: 99%

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Carbogen breathing with nicotinamide improves the oxygen status of tumours in patients

Laurence

Ward²,

Dennis³

et al. 1995

Br J Cancer

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Section: Dimsciosupporting

confidence: 77%

mentioning

confidence: 99%

Carbogen breathing with nicotinamide improves the oxygen status of tumours in patients

Laurence

Ward²,

Dennis³

et al. 1995

Br J Cancer

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“…All but one had mean plasma levels greater than 900 nmol/ml at the time, of iiTadiations. It was shown that peak plasma levels are linearly dependent on the administered drug dose [8,18,19]. If levels of at least 900 nmol/ml can be obtained with 80 mg/kg, the expected minimum level after a 25% reduction of dose would be around 700 nmol/ml or slightly lower.…”

Section: 4 Dose Reduction Imentioning

confidence: 99%

“…Large inter-patient variations in Cm ax were seen however. We used a liquid formulation which, on average, produced higher peak levels than tablets which were used in other studies [9,19] and also shorter Timx with a mean of 0.83 h (SD ±0.73) as compared to 2.1 h (SD ±L3) with tablets [9]. Apparently the drug is more rapidly absorbed when administered as a liquid formulation resulting in higher Cmax.…”

Section: J Tolerancementioning

confidence: 99%

“…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%

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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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Impact of Pregnancy on the Pharmacokinetics and Metabolism of Nicotinamide in Humans

Fashe,

Le,

Gower

et al. 2024

Clin Pharma and Therapeutics

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In preeclampsia models, nicotinamide (NAM) has protective effects in preeclampsia and is being evaluated as a therapeutic nutraceutical in clinical studies. NAM undergoes extensive hepatic metabolism by NAM N‐methyltransferase to methylnicotinamide (MNA), which is subsequently metabolized to methyl‐2‐pyridone‐5‐carboxamide (M2PY) by aldehyde oxidase. However, the pharmacokinetics (PK) of NAM and its major metabolites has never been studied in pregnant individuals. Blood samples were collected before and 1, 2, 4, 8, and 24 hr after single 1g oral NAM dose in healthy pregnant (gestational age 24‐33 weeks) and nonpregnant female volunteers (n=6/group). Pooled urine was collected from 0‐8 hr. NAM, MNA and M2PY area under the concentration‐time curve (AUC) data were analyzed by noncompartmental analysis. No difference in the plasma AUC0→24 of NAM (median [25%‐75%]: 463 [436‐576] vs 510 [423, 725] μM*hr, p=0.430) and its intermediate metabolite MNA (89.1 [60.4, 124.4] vs 83.8 [62.7, 93.7] μM*hr, p=0.515) was observed in pregnant and nonpregnant volunteers, respectively; however, the terminal metabolite M2PY AUC0→24 was significantly lower in pregnant individuals (218 [188, 254] vs 597 [460, 653] μM*hr, p<0.001). NAM renal clearance (CLR) (p=0.184), MNA CLR (p=0.180), and total metabolite formation clearance (CLform) (p=0.405) did not differ across groups; however, M2PY CLR was significantly higher in pregnant individuals (10.5 [9.3‐11.3] vs 7.5 [6.4‐8.5] L/hr, p=0.002). These findings demonstrate that the PK of NAM and systemic exposure to its intermediate metabolite MNA are not significantly altered during pregnancy, and systemic exposure to NAM's major metabolite M2PY was reduced during pregnancy due to increased renal elimination.

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Pharmacokinetics of nicotinamide and its effect on blood pressure, pulse and body temperature in normal human volunteers

Cited by 65 publications

References 16 publications

Carbogen breathing with nicotinamide improves the oxygen status of tumours in patients

Carbogen breathing with nicotinamide improves the oxygen status of tumours in patients

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

Impact of Pregnancy on the Pharmacokinetics and Metabolism of Nicotinamide in Humans

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