Aspartame pharmacokinetics - the effect of ageing.

Aspartame is an intense sweetener which is increasingly used in the UK. It is registered at an acceptable daily intake (ADI) of 40 mg/kg, although there are no previous data relating to the metabolism of aspartame in older people. Twelve young and 12 elderly volunteers each received a single dose of approximately 40 mg/kg of aspartame. Baseline concentrations of phenylalanine (the main metabolite of aspartame) rose after ingestion with a significantly higher maximum concentration (Cmax) (81.3 vs. 63.3 micromol/1, p<0.01) and area under the plasma concentration-time curve extrapolated to infinity AUC 9(0-infinity)(518.7 vs. 353.5 micromol . h/l, p<0.01) in the elderly group. The higher concentrations reflected a significant fall in volume of distribution (V) from 2.03 to 1.59 1/kg (p <0.05) and clearance (CL) from 7.3 to 4.9 ml/min/kg (p <0.005) in the elderly group. The greater effect on CL than on V resulted in a small but non-significant rise in elimination half life (3.5 to 3.9 hours). The sizes of the differences were modest implying that there is no need on pharmacokinetic grounds for a change in the ADI for older people.

Indomethacin and protein binding of methotrexate.

Indomethacin, a non-steroidal anti-inflammatory drug is known to increase the efficacy and toxicity of methotrexate, the widely used anti-cancer drug in man. The mechanism for this interaction has not been clearly established. However, since these drugs bind with albumin, a possible displacement of methotrexate by indomethacin from albumin might explain this interaction. To investigate the possible interaction an in-vitro protein-binding displacement study was carried out in 17 normal volunteers and in two groups of eight cancer patients. One group of patients had active disease and the other was in complete clinical remission. Serum samples were obtained and protein levels estimated. The protein binding of methotrexate was measured alone and with indomethacin using equilibrium dialysis. Statistical analysis of results suggested that the binding of methotrexate is not influenced by indomethacin, confirming that methotrexate is not displaced by indomethacin.

Protein binding of indomethacin, methotrexate and morphine in patients with cancer.

The in vitro protein binding of indomethacin, morphine and methotrexate has been studied in two groups of ten patients each suffering from different types of cancers and compared with twenty normal adult subjects. One group of patients had active disease and the other group was in complete clinical remission. Serum samples were obtained from each subject and the concentrations of albumin and alpha-1 acid glycoprotein (AGP) were measured. Protein binding of drugs was determined using equilibrium dialysis. Alpha-1 acid glycoprotein levels were increased in patients and this effect was more pronounced in active disease (1802 +/- 1025 mg/l) than in remission (931 +/- 273 mg/l). Albumin levels were reduced in active disease (47.67 +/- 15.91 milligrams), but not in remission (61.86 +/- 6.62 milligrams), as compared to control values (58.98 +/- 9.9 milligrams). The protein binding of methotrexate and indomethacin were both reduced in active disease (34.17 +/- 7.12% and 96.26 +/- 0.93% respectively) in comparison with normal subjects (39.33 +/- 4.68% and 96.89 +/- 0.47% respectively), but that of morphine was not changed. In patients there was a strong negative correlation between albumin and alpha-1 acid glycoprotein levels (r = -0.75, p < 0.01) but the correlation in controls was not significant. This study found only weak association between the binding of the drugs studied and the protein levels. It is concluded that reduction in methotrexate dose levels may reduce toxicity in patients with active cancer.