Pharmacokinetics of trimetrexate (NSC 352122) in monkeys.

The pharmacokinetics of trimetrexate was studied in Rhesus monkeys following i.v. bolus, continuous i.v. infusion, oral, and subcutaneous administration. Two methods were used to measure drug concentration in plasma, cerebrospinal fluid (CSF), and urine: the dihydrofolate reductase inhibition assay, and a reverse phase high-pressure liquid chromatography assay. The pharmacokinetic behavior of trimetrexate was characterized by triexponential plasma disappearance, elimination primarily by biotransformation, substantial plasma protein binding, poor CSF penetration, and limited oral bioavailability. Methotrexate, administered in an equimolar dose for comparison, was cleared more rapidly from plasma than was trimetrexate. Trimetrexate concentration remained above 0.1 microM 3-fold longer. In contrast to methotrexate, which is cleared almost exclusively by renal excretion, renal clearance of trimetrexate accounted for less than 5% of total clearance. A significant discrepancy was observed in plasma and urine trimetrexate concentrations measured by the two assay methods. The dihydrofolate reductase inhibition assay gave results approximately 2- to 4-fold higher in plasma. Two metabolites of trimetrexate which inhibit dihydrofolate reductase were identified in urine (one was also found in plasma) and appear to account for the different results obtained by the two assays. These metabolites would probably also interfere with the competitive protein binding assay currently being used to measure trimetrexate in ongoing phase I trials.

Intrathecal administration of 4-hydroperoxycyclophosphamide in rhesus monkeys.

The preactivated cyclophosphamide analogue, 4-HC, does not require activation by hepatic microsomal enzymes to express its cytotoxic activity and therefore, unlike cyclophosphamide, may be useful for the regional therapy of cancer. In the present study, the pharmacokinetics and toxicology of 4-HC were studied following intraventricular administration of 0.4 mg to rhesus monkeys with chronic indwelling Ommaya reservoirs. 4-HC was measured in cerebrospinal fluid (CSF) and plasma with a high-performance liquid chromatography assay utilizing a fluorometric detector following derivatization with m-aminophenol. The mean peak level of 4-HC in ventricular CSF was 100 microM 5 min after administration. The drug was cleared rapidly and the elimination was monoexponential with a mean half-life of 22 min. The mean clearance from CSF (0.33 ml/min) was 10-fold higher than CSF bulk flow. The drug was distributed throughout the subarachnoid space with lumbar levels approaching ventricular levels by 60 min. Neither acute nor chronic neurotoxicity or systemic toxicity was observed during the 6-wk observation period. Concentrations of 4-HC demonstrated to be cytocidal in vitro against human breast cancer, lymphoid leukemia, and rhabdomyosarcoma were readily achieved in CSF following intraventricular administration. This study demonstrates that intraventricular therapy with 4-HC is feasible and suggests that further study of this approach in the clinical setting should be considered.

Pharmacokinetics of tiazofurin in the plasma and cerebrospinal fluid of rhesus monkeys.

The pharmacokinetic disposition of tiazofurin in plasma and cerebrospinal fluid was examined in rhesus monkeys. Tiazofurin was readily detectable in both plasma and cerebrospinal fluid within 20 min of commencement and for 24 h after a short i.v. infusion of the drug. The mean clearance of tiazofurin from plasma was 70 +/- 23 (SD) ml/min/sq m after a dose of 100 mg/kg and 106 +/- 38 ml/min/sq m after a dose of 500 mg/kg with no evidence of dose dependency. The data for plasma elimination of tiazofurin were fit to a triexponential equation for comparison with data from other species. The t 1/2 alpha was 0.23 h, t 1/2 beta was 1.9 to 2.0 h, and t 1/2 gamma was 6.8 to 7.1 h. The ratio of area under the cerebrospinal fluid drug concentration-time curve to the area under the plasma drug concentration-time curve was 0.28, which suggests significant penetration of the blood-brain barrier. These results demonstrate the propensity of tiazofurin to enter the cerebrospinal fluid and, probably, the brain, and suggest a potential role for this agent in the treatment of central nervous system cancer.

Differences in cerebrospinal fluid penetration of corticosteroids: possible relationship to the prevention of meningeal leukemia.

The disposition of the synthetic corticosteroids, dexamethasone and prednisolone, in CSF was evaluated following bolus intravenous (IV) and intrathecal (IT) injection in a nonhuman primate model. Steroid concentration in plasma and CSF was measured with a radioimmunoassay following celite column chromatography. The CSF to plasma ratios of dexamethasone and prednisolone following IV bolus administration were 0.15 +/- 0.02 and 0.08 +/- 0.03, respectively. Although peak levels of the two steroids in the CSF reached equally potent levels when administered systemically in equipotent doses, the half-life of prednisolone in the CSF was shorter. In addition, there was a significant difference in the plasma protein binding of the two steroids, which may account for the differences in their CSF pharmacokinetics. Dexamethasone was 70% protein bound over a wide concentration range, while the protein binding of prednisolone was concentration dependent, ranging from 60% at 10 mumol/L to 95% at 0.5 mumol/L and below. After the initial distribution phase in plasma, CSF concentrations of dexamethasone and prednisolone approximated free plasma concentrations, indicating that penetration into the CSF was limited primarily by protein binding. At the plasma concentrations achieved following oral administration of standard doses of prednisone in children, the prednisolone (the active metabolite) is greater than 90% protein bound. The proportionally higher free plasma levels of dexamethasone result in greater penetration into the CSF. These findings may explain the lower rates of meningeal leukemia observed in children receiving dexamethasone instead of prednisone for the treatment of acute lymphoblastic leukemia (ALL).

The effect of amitriptyline on the central nervous system penetration of methotrexate.

The reported ability of amitriptyline to enhance the penetration of diffusion limited substances across the blood brain barrier was investigated. The CSF:plasma ratio of methotrexate in primates was not significantly altered by amitriptyline pretreatment. Nor was methotrexate plasma clearance altered.

The influence of route of administration on the hepatic uptake of methotrexate.

The present study was designed to determine if the hepatic toxicity of chronic low-dose methotrexate could be circumvented by administering the drug systemically, avoiding high initial hepatic drug exposure resulting from absorption of an oral dose into the portal circulation. Hepatic concentrations of methotrexate were determined in rats following chronic administration of 1 mg/kg by either the intraperitoneal (absorbed via the portal circulation) or subcutaneous route. Plasma drug profiles of methotrexate administered by the two routes were similar. The mean (+/- S.D.) hepatic methotrexate concentration following intraperitoneal administration was 3.12 +/- .47 nmol/gm wet weight and following subcutaneous administration it was 2.68 +/- .52 (p = .06). Renal methotrexate concentrations in the 2 groups were 1.23 +/- .27 and 1.26 +/- .49 nmol/gm wet weight, respectively (p = .88). The results of this study suggest that that oral administration does not lead to greater accumulation of methotrexate in the liver compared to systemic administration.

Folate and methotrexate polyglutamate tissue levels in rhesus monkeys following chronic low-dose methotrexate.

Methotrexate (MTX), a mainstay in the treatment of acute lymphoblastic leukemia, is associated with both hepatic and neurologic toxicity. Like a folate, MTX is metabolized to polyglutamated derivatives (MTXGlun) with long intracellular half-lives. These metabolites may contribute to MTX toxicity through a direct effect on cellular metabolism or indirectly through a perturbation of folate homeostasis. To better define the effects of chronic MTX treatment, tissue levels of MTX, MTXGlun, and folate were measured in three monkeys treated with weekly intramuscular MTX for 1 year. Greater than 80% of the total tissue MTX found was in the form of polyglutamated derivatives. Most of these derivatives were MTXGlu3-5 but Glu6-7 were easily detectable. Total tissue folates were measured in liver, kidney, brain and testis with MTX treated animals having a 90% loss of total folate in brain tissue. This is of special interest since inborn errors of folate metabolism are often associated with severe neurologic abnormalities.

Developing a unit for mentally retarded-mentally ill patients on the grounds of a state hospital.

For some time patients with the dual diagnosis of mental retardation and mental illness have been recognized as a distinct patient population, but development of programs meeting their special needs is slow. In October 1986 a Massachusetts state psychiatric facility opened a rehabilitative program for such patients in a separate 40-bed unit on the hospital grounds. All patients admitted to the Specialized Habilitative and Rehabilitative Environment (SHARE) program had long histories of institutionalization, and many had been treated with neuroleptic drugs for several years. Most patients now attend day programming, and a few have been able to move on to less restrictive environments. Patients' average neuroleptic dosage has been substantially reduced. This progress has been made in spite of such program-development problems as the need to change staff's long-held perspectives about dual-diagnosis patients, lack of funding, and high staff turnover.