Interaction between phenytoin and valproic acid: plasma protein binding and metabolic effects.

The effect of sodium valproate (400 mg three times daily) on the disposition kinetics of intravenous phenytoin (250 mg) was investigated in seven normal subjects. After valproate, the free (unbound) fraction of phenytoin in serum rose from 9.6 +/- 0.9% (SD) to 15.6 +/- 1.4% on average (p < 0.001). The effect was associated with an increase in systemic clearance and apparent volume of distribution of total drug. There was a strong positive correlation between percent increment in each of these parameters and percent increment in unbound drug in serum. Free phenytoin concentration in serum and phenytoin concentration in saliva increased during valproate administration. As a result, both the clearance and the apparent volume of distribution of free drug were reduced. There was an increase in the renal excretion of unchanged phenytoin during valproate administration, but the effect was too small to have an appreciable influence on the overall clearance of the drug. There were no consistent changes in the excretion of the major metabolite 5, p-hydroxyphenyl, 5-phenyl, hydantoin (pHPPH), in the urine. These results suggest that valproic acid may have two separate and opposing effects on phenytoin disposition: (1) displacing phenytoin from plasma protein binding sites, thereby enhancing the systemic clearance of total drug, and (2) inhibiting phenytoin metabolism, thereby increasing the concentration of free drug in the serum.

Quality control in drug measurement.

Therapeutic drug monitoring of serum concentrations has become a rapidly expanding area of clinical pharmacology and is likely to remain an important growth area in the future, despite that the evidence for the efficacy of such monitoring is inconclusive except for a handful of drugs and findings that the reliability of much drug assay work is far from optimal. Nonetheless, in view of the likelihood that the use of routine monitoring will increase, the institution of quality control programs seems not only desirable, but necessary. We describe the design of Bartscontrol (formerly known as St. Bartholomew's Hospital Quality Control Scheme for Antiepileptic Drugs) and discuss the experience of this program. Although the feedback provided to the participants of such a program seems to encourage an overall increase in precision, our findings also indicate that some laboratories perform consistently badly. While the data generally do not reveal that variations in precision are due to analytical method employed, a scheme such as the one described can occasionally make the important finding that a particular technique is inappropriate, as was found for the case of spectrophotometry for phenytoin.

Water intoxication in epileptic patients receiving carbamazepine.

Plasma sodium and osmolality were determined in 80 adult epileptic patients receiving chronic treatment with carbamazepine and in 50 control patients treated with other anticonvulsant drugs. Mean plasma osmolality was significantly lower in the carbamazepine-treated patients but mean plasma sodium did not differ in the two groups. Hyponatraemia was found in five of the carbamazine-treated patients and hypo-osmolality in six. None of the control patients had hyponatraemia and only one had a borderline low osmolality. Three of the 13 patients receiving carbamazepine alone were hyponatraemic. Plasma sodium concentration correlated negatively with both daily carbamazepine dose and serum carbamazepine level. Free water clearance after an oral water load was determined in six patients on carbamazepine alone and in six normal subjects not receiving drug therapy. The capacity of some of the patients to excrete the water load was found to be grossly impaired.