PHARMACOKINETIC STUDY OF ZONISAMIDE IN PATIENTS UNDERGOING BRAIN SURGERY

To test whether the concentration of the anticonvulsant zonisamide in erythrocytes reflects the brain concentration and the clinical respons e of the drug, its pharmacokinetics were studied in nine patients unde rgoing surgery for brain tumour. Erythrocyte, total, and free serum co ncentrations in samples drawn on the day of brain surgery were compare d with levels on a day after the operation. In three patients zonisami de and its major metabolite, 2-sulphamoylacetylphenol, were also analy sed in urine. The area under the curve of the free and the erythrocyte concentration did not differ between the two study phases whereas the area under the curve of the total serum concentration was significant ly lower on the day of the operation, and this was associated with sig nificant increases in total clearance (15.4 compared with 12.7 mL kg(- 1) h(-1), P < 0.05, n = 9) and renal clearance (5.4 compared with 3.3 ml kg(-1) h(-1), P < 0.05, n = 3), and non-significant change in nonre nal clearance (7.7 on the day of operation compared with 8.4 ml kg(-1) h(-1) on the post-operation day, n = 3). Zonisamide distribution was also altered by the operative procedure, as evidenced by a higher volu me of distribution (1.48 compared with 0.87 L kg(-1), P < 0.05, n = 9) . The binding of zonisamide was characterized on both days. Zonisamide binding to erythrocytes seemed to occur by two processes: a saturable process and a non-saturable linear process. The maximum binding capac ity to erythrocytes (31.6 vs 29.7 mu g mL(-1)) did not differ on the t wo days; however, increases in the dissociation binding constant (+28% ) and the proportionality constant (+24%) were observed on the day of the operation, suggesting that the zonisamide concentration in erythro cytes was greater on the day of the operation. Brain surgery appears t o be one of the possible factors altering the rate of elimination of z onisamide and the uptake of the drug by erythrocytes.