Central Nervous System Pharmacokinetics Research Articles

Blood and cerebrospinal fluid pharmacokinetics of primidone and its primary pharmacologically active metabolites, phenobarbital and phenylethylmalonamide in the rat.

Primidone is a clinically useful antiepileptic drug that is metabolised to two pharmacologically active metabolites phenobarbital and phenylethylmalonamide. As data on the inter-relationship between the systemic and central nervous system pharmacokinetics of primidone and its metabolites are sparse, we have investigated their temporal inter-relationship using a freely behaving rat model which allows repeated sampling of blood (100 microl) and cerebrospinal fluid (CSF; 20 microl). After administration, by intraperitoneal injection (50, 100 or 200 mg/kg), primidone rapidly appeared in both serum (Tmax mean range 1.5-2.5 h) and CSF (Tmax mean range 2.0-3.5 h), suggesting ready penetration of the blood-brain-barrier. This was also the case for phenylethylmalonamide and phenobarbital but peak concentration occurred later. Primidone, phenylethylmalonamide and phenobarbital concentrations rose linearly and dose-dependently in both serum and CSF. The mean free fraction (free/total concentration ratio) for primidone, phenylethylmalonamide and phenobarbital was 0.86, 0.97 and 0.88, respectively, and, as their respective mean CSF/serum ratio values were 0.73, 1.06 and 0.65, it would suggest that equilibration between the blood and CSF compartments is rapid. CSF mean t(1/2) values for primidone, phenylethylmalonamide and phenobarbital were similar to those of sera and essentially paralleled the pattern seen in sera.

Pharmacologic strategies for the treatment of meningeal malignancy.

There have been significant strides in the treatment and prevention of meningeal cancer, particularly meningeal leukemia, during the past thirty years. These advantages are a direct result of innovative therapeutic approaches specifically designed to overcome the limitations of systemically administered chemotherapy. Such approaches include the administration of intrathecal chemotherapy by intralumbar or intraventricular injection, the administration of very high-dose systemic chemotherapy, and the administration of cranial or craniospinal irradiation. A better understanding of the central nervous system pharmacokinetics of commonly used anticancer agents has also resulted in improvements in the treatment of meningeal cancer. In this article, the clinical pharmacology of the most commonly used intrathecal agents and pharmacologic strategies for the treatment of meningeal cancer will be discussed. In addition, an overview of new agents for intrathecal administration and other novel CNS targeted therapies will be presented.

Central nervous system pharmacokinetics of high-dose cytosine arabinoside.

The cerebrospinal fluid (CSF) pharmacokinetics of cytosine arabinoside (Ara-C) was determined in 8 patients with metastatic cancer in the central nervous system. High dose (3 gm/M2) one-hour intravenous infusions of Ara-C were given with serial CSF sampling obtained from indwelling Ommaya reservoirs. CSF was analyzed by high pressure liquid chromatography. Mean Ara-C elimination half life of 140 minutes in CSF was eight times longer than that in plasma. The peak mean CSF concentration of Ara-C (2.1 micrograms /ml) was about 7% of the plasma concentration (30 micrograms/ml). A total of 28 treatment courses were administered with minimal hematopoietic, gastrointestinal and neurological toxicities. A schedule of administration of 2 high-dose treatments 12 hours apart repeated every two weeks should maintain cytotoxic CSF concentrations which could prove useful in the management of CNS leukemia and lymphoma.

Carrier-mediated blood-brain barrier transport of short-chain monocarboxylic organic acids

Carrier-mediated blood-brain barrier transport of short-chain monocarboxylic organic acids