The binding of amsacrine to human plasma proteins.

Determination of amsacrine plasma protein binding by both equilibrium dialysis and ultracentrifugation gave similar results and indicated that amsacrine is highly bound (approximately 97%) in human plasma. This binding is independent of amsacrine concentration over the range 1-100 mumol litre-1, but is very sensitive to plasma pH and, to a lesser extent, to temperature. Approximately 20% of the drug appeared to be covalently bound to plasma proteins. Amsacrine was bound by all plasma proteins investigated including albumin, alpha 1-acid glycoprotein and various gamma-globulins. The binding to albumin appeared to occur by two processes, a saturable process at a single site with a KD of 13.9 mumol litre-1 and a non-saturable process. Despite differences in individual protein concentrations, no significant difference was observed in the unbound amsacrine fraction in plasma from patients receiving this drug for treatment of acute myelogenous leukaemia and plasma from healthy individuals.

Prevalence of toxic anticonvulsant drug concentrations in mentally retarded persons with epilepsy.

Anticonvulsant drug concentrations in retarded individuals (117 hospital residents, 58 community-based) were surveyed. Concentrations of carbamazepine (CBZ, Tegretol) and phenytoin (Dilantin) were determined in salivary samples collected before morning medication (premedication sample) and 4 hours later (postmedication sample). Of 146 individuals receiving CBZ, 16% had salivary concentrations above the therapeutic range on at least one sample, whereas 2% exceeded the range on both samples. Of the 54 subjects prescribed phenytoin, 28% had at least one salivary concentration exceeding the therapeutic range, and 15% surpassed the therapeutic range on both samples. These data suggest the desirability of using regular therapeutic drug monitoring and neurological assessments to avoid the possibility of toxic drug levels in this population. A variety of subject and pharmacological variables (sex, severity of retardation, number of seizures in the last year, and dose) were also examined for their relationship to drug concentrations.

The effect of buthionine sulphoximine, cimetidine and phenobarbitone on the disposition of amsacrine in the rabbit.

Evidence suggests that the main elimination pathway for amsacrine is hepatic oxidation to the quinone diimine derivative followed by conjugation with glutathione (GSH) and excretion in the bile. If this is so, amsacrine elimination should be susceptible to induction by phenobarbitone (PB) and inhibition by cimetidine (CT) and perhaps by buthionine sulphoximine (BSO), a specific depleter of tissue GSH. This study was carried out in groups of six rabbits. Each rabbit acted as its own control and received pretreatment with saline or PB, CT, or BSO, followed by an amsacrine infusion. Blood (8 X 3 mL) was collected up to 12 h and total plasma amsacrine concentrations determined by HPLC. PB pretreatment resulted in a significant increase in amsacrine's Cl (mean 46%, range 25%-70%) and also in the Vd (mean 58%, range 25%-117%), but had no effect on t1/2 alpha, t1/2 beta or MRTni. In addition, there was no change in the plasma protein binding of amsacrine after PB pretreatment. CT pretreatment had the opposite effect, resulting in a significant decrease in amsacrine's Cl (mean 33%, range 21%-38%) and a decrease in Vd, although this latter decrease was not significant at the 5% level. As with PB, the time parameters were not significantly changed. BSO pretreatment resulted in a significantly reduced Cl (mean 22%, range 15%-30%), no effect on Vd or on t1/2 alpha, but significantly prolonged t1/2 beta and MRTni. BSO pretreatment was also associated with a significant reduction in red blood cell GSH concentration. These results are consistent with the involvement of the hepatic mixed function oxidase system and GSH status in the elimination of amsacrine in the rabbit.

No impairment of antipyrine elimination by the selective anticholinergic drug pirenzepine.

The elimination kinetics of antipyrine have been established under basal environmental conditions in 6 healthy volunteers. Concentrations of antipyrine in serum were measured by a relatively fast high-pressure liquid chromatography method using a radial-compression chromatographic system. Pretreatment of the subjects with therapeutic doses of pirenzepine over 5 days had no significant effect on the absorption, distribution, and elimination of antipyrine. These results suggest that pirenzepine is free of the inhibition of the hepatic mixed function oxidase system produced by cimetidine.

Sodium valproate (Epilim) in epilepsy: a trial.

Of thirty-five patients with various types of epilepsy treated with sodium valproate, 15 achieved complete seizure control on that drug alone, 12 other patients benefited and eight failed to improve on the drug. Excellent results were more likely in those with petit mal epilepsy and in those whose epilepsy was controlled with other drugs at the expense of side effects. Three patients were unable to tolerate valproate, but in general few patients experienced side effects and several patients felt much better on valproate than on their previous drugs. A twice daily dosage regime was satisfactory. Plasma valproate levels at the final dose covered a wide range, 0.21 - 1.2mmol/l (34 to 190 microgram/ml) and did not correlate with response, lack of response or side effects.