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.     

Effects of rifampicin and cimetidine on pharmacokinetics and pharmacodynamics of lamotrigine in healthy subjects

OBJECTIVE: To study the effects of rifampicin, a potent inducer of the microsomal P450 enzyme system and of specific isoforms of the uridine 5'-diphosphate(UDP)-glucuronyl-transferase enzyme system, and cimetidine, a known inhibitor of the hepatic microsomal cytochrome P450 enzyme system, on pharmacokinetics and pharmacodynamics of lamotrigine in healthy subjects. METHODS: Ten healthy male subjects received a single oral dose of 25 mg lamotrigine after a 5-day pretreatment with (1) cimetidine 800 mg divided into two equal doses, (2) rifampicin 600 mg, or (3) placebo. Serum and urine samples were analyzed using high-performance liquid chromatography. Changes in electroencephalographic (EEG) power were determined up to 48 h after lamotrigine administration. RESULTS: The values of the pharmacokinetic parameters of lamotrigine were: clearance over bioavailability (CL/F) 2.60+/-0.40 l/h, renal clearance (CLR) 0.10+/-0.03 l/h, terminal half-life (t1/2) 23.8+/-2.1 h, mean peak serum concentration (Cmax) 0.29+/-0.02 microg/l, time to reach Cmax (tmax) 1.6+/-0.28 h, and total area under the serum concentration-time curve (AUC0-infinity) 703.99+/-82.31 microg/ ml/min (mean +/- SEM). The amount of lamotrigine excreted as glucuronide was 8.90+/-0.77 mg. Rifampicin significantly increased CL/F (5.13+/-1.05 l/h) and the amount of lamotrigine excreted as glucuronide (12.12+/-0.94 mg), whereas both t1/2 (14.1+/-1.7 h) and AUC(0-infinity) (396.24+/-60.18 microg/ml/min) were decreased (P<0.05). Cimetidine failed to affect pharmacokinetics of lamotrigine. Lamotrigine did not change EEG power. CONCLUSION: Rifampicin altered pharmacokinetics of lamotrigine due to induction of the hepatic enzymes responsible for glucuronidation, while coadministration of cimetidine to ongoing lamotrigine therapy has negligible effects on lamotrigine pharmacokinetics. Lamotrigine administered as a single dose of 25 mg has no effect on EEG power in healthy subjects.     

A microdialysis study of the novel antiepileptic drug levetiracetam: extracellular pharmacokinetics and effect on taurine in rat brain.

Using a rat model which allows serial blood sampling and concurrent brain microdialysis sampling, we have investigated the temporal kinetic inter-relationship of levetiracetam in serum and brain extracellular fluid (frontal cortex and hippocampus) following systemic administration of levetiracetam, a new antiepileptic drug. Concurrent extracellular amino acid concentrations were also determined. After administration (40 or 80 mg kg(-1)), levetiracetam rapidly appeared in both serum (T(max), 0.4 - 0.7 h) and extracellular fluid (T(max), 2.0 - 2.5 h) and concentrations rose linearly and dose-dependently, suggesting that transport across the blood-brain barrier is rapid and not rate-limiting. The serum free fraction (free/total serum concentration ratio; mean+/-s.e.mean range 0.93 - 1.05) was independent of concentration and confirms that levetiracetam is not bound to blood proteins. The kinetic profiles for the hippocampus and frontal cortex were indistinguishable suggesting that levetiracetam distribution in the brain is not brain region specific. However, t(1/2) values were significantly larger than those for serum (mean range, 3.0 - 3.3 h vs 2.1 - 2.3 h) and concentrations did not attain equilibrium with respect to serum. Levetiracetam (80 mg kg(-1)) was associated with a significant reduction in taurine in the hippocampus and frontal cortex. Other amino acids were unaffected by levetiracetam. Levetiracetam readily and rapidly enters the brain without regional specificity. Its prolonged efflux from and slow equilibration within the brain may explain, in part, its long duration of action. The concurrent changes in taurine may contribute to its mechanism of action.     

The plasma pharmacokinetics and cerebral spinal fluid penetration of intravenous topiramate in newborn pigs

INTRODUCTION: Pre-clinical studies suggest that the anticonvulsant topiramate confers neurologic protection against ischemia. An intravenous formulation of topiramate has been developed for administration during conditions such as hypoxia-ischemia when enteral absorption may be unpredictable. The plasma pharmacokinetics, cerebrospinal fluid (CSF) penetration and pharmacodynamics of intravenous topiramate were studied in an established piglet model of hypoxia-ischemia. METHODS: The plasma pharmacokinetics of topiramate were studied in a group of chronically instrumented conscious piglets (n = 8), and in a group of piglets following an episode of hypoxia-ischemia (n = 8). These groups were divided into equal dose cohorts in which two doses of intravenously administered topiramate, 5 and 40 mg/kg, were studied. The animals' heart rate, arterial pressure and EEG were monitored. Plasma for topiramate concentration was sampled for up to 26 h. A single CSF topiramate concentration was determined 1 h following drug administration. Topiramate was quantified using a specific LC/MS assay. RESULTS: The animals tolerated intravenous topiramate well, with no significant changes in physiologic and neurologic parameters. Plasma topiramate concentrations following an intravenous dose were best described by a bi-exponential equation, with a mean clearance of 39+/-18 ml/h/kg, and a terminal half-life of 14.3 (range 7.5-48.1) h. A dose of 5 mg/kg was sufficient to maintain plasma drug concentrations greater than 10 micro M for 24 h. CSF topiramate concentration at 1 h was 12+/-1 micro M and 109+/-26 micro M at the 5 and 40 mg/kg doses, respectively. CONCLUSION: Topiramate administered intravenously was well tolerated. Slow clearance of the drug allowed for maintenance of potential neuroprotective concentrations following a single dose of drug for 24 h. High drug penetration into the CSF is an ideal pharmacologic characteristic of any potential neuroprotective agent. The pharmacokinetic profile of intravenously administered topiramate, including its penetration into the CSF, appears to achieve this goal.     

Pharmacokinetics of cytosine arabinoside, methotrexate, nimustine and valproic acid in cerebrospinal fluid during cerebrospinal fluid perfusion chemotherapy

This report investigates the pharmacokinetics of cytosine arabinoside (Ara-C), methotrexate (MTX), nimustine (ACNU) and valproic acid (VPA) in cerebrospinal fluid (CSF) during CSF perfusion chemotherapy. A 28-year-old Japanese woman with disseminated glioblastoma was, on admission, on a stable oral regimen of prolonged-release VPA tablets (Depakene-R), 400 mg twice a day, for seizure control. Twelve courses of CSF perfusion chemotherapy with Ara-C, MTX, and ACNU were administered. Plasma samples and CSF samples via Ommaya reservoirs were obtained during the eleventh course of treatment. The Ara-C and ACNU concentrations were measured by HPLC. The MTX and VPA concentrations were measured by fluorescence polarization immunoassay. During CSF perfusion chemotherapy, the highest CSF concentrations of Ara-C, MTX, and ACNU were observed at the end of the perfusion and decreased in a monoexponential pattern. The half-lives of Ara-C, MTX, and ACNU were 2.65, 3.52, and 0.71 h, respectively. No anticancer drugs were detectable in plasma during CSF perfusion chemotherapy. Before CSF perfusion chemotherapy, the free VPA concentration in plasma was 14.4% of the total VPA concentration. The mean total and free VPA concentrations in plasma were 78.0+/-0.8 and 10.9-0.3 microg/ml, respectively. The free VPA concentrations in plasma and in CSF were of similar values. At the end of perfusion, the lowest free VPA concentration in CSF was 30.3% of that at the initiation of perfusion. The free VPA concentrations in CSF at 3, 7, 23, and 47 h after the end of perfusion were 79.8, 94.5, 100.9, and 100.9% respectively of that at the initiation of perfusion. During CSF perfusion chemotherapy, the ratio of free VPA concentrations to the total VPA in CSF was 86.3+/-6.9%. The VPA concentrations in CSF rapidly decreased during the CSF perfusion but recovered to pre-treatment levels within 7 h.     

Cerebrospinal fluid pharmacokinetics of cefpodoxime proxetil in piglets

Cefpodoxime is an oral third-generation cephalosporin used for the treatment of acute upper-respiratory tract infections caused by susceptible bacteria in children. Although not indicated for the treatment of bacterial meningitis, it is used to treat other infections produced by organisms associated with meningitis and may obscure the result of cerebrospinal fluid (CSF) cultures in children who develop meningitis while receiving oral antibiotics if sufficient concentrations are achieved in the CSF. This study evaluated the disposition of cefpodoxime and penetration into CSF in piglets. Fifteen Landacre-Camborough cross piglets (10-20 days old) received cefpodoxime proxetil oral suspension (10 mg/kg). Repeated plasma and CSF samples were collected over 24 hours for quantitation of cefpodoxime by HPLC. Pharmacokinetic analysis was performed on both plasma and CSF data. The plasma concentration versus time data for cefpodoxime were best characterized using a one-compartment model with first-order absorption. The mean (+/- SD) pharmacokinetic parameters for Cmax, tmax, and AUC0-infinity were 23.3 +/- 12.9 mg/L, 3.9 +/- 1.4 h, and 237 +/- 129 mg/L.h, respectively. CSF/plasma ratios for AUC0-infinity demonstrated a mean cefpodoxime penetration of approximately 5%. CSF penetration of cefpodoxime was evident following a single oral dose of cefpodoxime proxetil suspension. Despite the small percentage of total cefpodoxime dose distributing into the CSF, the resultant concentrations approached or exceeded the MIC90 for many bacterial pathogens considered susceptible to cefpodoxime. Accordingly, clinicians should use caution in the interpretation of CSF cultures in patients who develop clinical signs and symptoms consistent with meningitis and who have been previously treated with cefpodoxime.     

Plasma concentration of topiramate correlates with cerebrospinal fluid concentration

The authors examined the ratio between the plasma and the cerebrospinal fluid (CSF) concentration of topiramate in 14 adults with epilepsy. Simultaneous trough samples of venous blood and CSF were collected and analyzed as total and unbound concentrations. Concomitant levels were also analyzed of lamotrigine (n = 5) and the relevant oxcarbazepine metabolite, 10-hydroxycarbazepine (n = 3). There was a close correlation between the plasma and the CSF concentration for both the total and unbound concentration of topiramate. The median CSF/plasma ratio of total topiramate was 0.85. The free topiramate concentration in plasma was not different from the free topiramate concentration in CSF. The CSF/plasma ratios showed little variation and were independent of the plasma level for both the total and the unbound levels. The unbound fraction of topiramate was 84% in plasma and 97% in CSF. The CSF concentrations of lamotrigine and 10-hydroxycarbazepine were 50% and 61% of the plasma concentrations, respectively. For topiramate, there is a close correlation between the plasma concentration and the CSF concentration. There does not seem to be a saturable carrier mechanism restricting topiramate transport across the blood-brain barrier. The concentration of topiramate in CSF is equal to the unbound proportion of topiramate in plasma, implying that the delivery of topiramate to the brain occurs via transfer from the unbound plasma pool. Plasma is thus a relevant matrix for therapeutic drug monitoring of topiramate.     

A pharmacokinetic study of diphenhydramine transport across the blood-brain barrier in adult sheep: potential involvement of a carrier-mediated mechanism.

The purpose of this study was to examine the disposition of diphenhydramine (DPHM) across the ovine blood-brain barrier (BBB). In six adult sheep, we characterized the central nervous system (CNS) pharmacokinetics of DPHM in brain extracellular fluid (ECF) and cerebrospinal fluid (CSF) using microdialysis in two experiments. In the first experiment, DPHM was administered via a five-step i.v. infusion (1.5, 5.5, 9.5, 13.5, and 17.5 microg/kg/min; 7 h per step). Average steady-state CNS/total plasma concentration ratios (i.e., [CNS]/[total plasma]) for steps 1 to 5 ranged from 0.4 to 0.5. However, average steady-state [CNS]/[free plasma] ratios ranged from 2 to 3, suggesting active transport of DPHM into the CNS. Plasma protein binding averaged 86.1 +/- 2.3% (mean +/- S.D.) and was not altered with increasing drug dose. Plasma, CSF, and ECF demonstrated biexponential pharmacokinetics with terminal elimination half-lives (t1/2beta) of 10.8 +/- 5.4, 3.6 +/- 1.0, and 5.3 +/- 4.2 h, respectively. The bulk flow of CSF and transport-mediated efflux of DPHM may explain the observed higher CNS clearances. In the second experiment, DPHM was coadministered with propranolol (PRN) to examine its effect on blood-brain CSF and blood-brain ECF DPHM relationships. Plasma total DPHM concentration decreased by 12.8 +/- 6.3% during PRN, whereas ECF and CSF concentrations increased (88.1 +/- 45.4 and 91.6 +/- 34.3%, respectively). This increase may be due to the inhibitory effect of PRN on a transporter-mediated efflux mechanism for DPHM brain elimination.     

Limited cerebrospinal fluid penetration of docetaxel

Our purpose was to investigate the cerebrospinal fluid (CSF) penetration of docetaxel in cancer patients. Docetaxel was administered as a 1-h infusion at a dose of 75 mg/m2 to two patients with metastatic breast cancer and leptomeningeal carcinomatosis. CSF samples were obtained using a lumbar puncture up to a 72-h time period. Total and unbound docetaxel concentrations in plasma and CSF were determined by liquid chromatography (lower limit of quantitation: 0.5 nM for plasma and 0.050 nM for CSF) and equilibrium dialysis, respectively. The pharmacokinetics of docetaxel in plasma are in line with data of previous studies. The concentrations of docetaxel in CSF did not follow the general pattern in plasma, with relatively stable concentrations over the 72-h time period. The fraction of unbound docetaxel in plasma ranged from 6 to 13%, while that in CSF ranged from 67 to 103%. For total and unbound docetaxel, the CSF to plasma concentration ratio progressively increased in 72 h from 0.01 to 0.6% and from 0.1 to 9%, respectively. These data suggest that measurement of unbound docetaxel is required to accurately assess the extent of drug penetration into CSF and that the drug can produce distribution to CSF at levels associated with significant antitumor activity in experimental models.     

Saliva and serum concentration of lamotrigine in patients with epilepsy

The authors examined the interindividual correlation between saliva and serum concentrations of lamotrigine (LTG) and the relationship between LTG concentration in saliva and the free LTG concentration in serum in 40 patients with epilepsy, aged 16 to 73 years, receiving stable doses of LTG and comedication. Saliva was collected before and after stimulation of salivary flow. The free LTG fraction was determined by equilibrium dialysis and ultrafiltration. Drug analysis was performed by high-performance liquid chromatography. The correlation between LTG daily dose and serum concentration was weak but significant (r = 0.47). There was high correlation between LTG concentration in serum and unstimulated (r = 0.85) or stimulated (r = 0.94) saliva, and between total LTG concentration in serum and the free LTG fraction as determined by ultrafiltration (r = 0.95) and equilibrium dialysis (r = 0.93). Lamotrigine concentration in stimulated saliva was significantly correlated to the free LTG fraction. Protein binding of LTG calculated from concentration in stimulated saliva, as determined by ultrafiltration and equilibrium dialysis, was 51.8% +/- 13.03%, 68.05% +/- 7.59%, and 58.72% +/- 7.68% (mean +/- standard deviation) respectively. The differences between the three methods were significant. The authors conclude that saliva sampling may be a useful alternative to blood tests for monitoring LTG treatment.     

Penetration of lidocaine and its active desethylated metabolite into cerebrospinal fluid in man

Summary Penetration into lumbar cerebrospinal fluid (CSF) of lidocaine and its active desethylated metabolite, monoethylglycinxylidide (MEGX), has been studied in 10 neurological patients after a single subcutaneous injection of 2 mg/kg prior to lumbar puncture. An HPLC method was used to assay lidocaine, MEGX and glycinxylidide (GX) in serum and CSF. The serum protein unbound fraction of lidocaine was determined by equilibrium dialysis. The mean peak serum lidocaine concentration was found 25 minutes after injection, and the corresponding peak CSF level occurred after 70 min. A similar slow penetration of MEGX into CSF was observed, which indicates low membrane permeability for these two agents. No GX was found. The steadily increasing CSF lidocaine/serum total lidocaine ratio throughout the period of study up to 120 min and the higher level in CSF than the corresponding unbound fraction of the total serum lidocaine indicate that serum protein binding is not the sole determinant of the penetration of lidocaine into lumbar CSF. Rapid accumulation in brain tissue and diffusion back into cerebral extracellular fluid and to lumbar CSF may also occur. The apparent slow membrane penetration of lidocaine and its desethylated metabolite may be one reason for the difficulty of controlling lidocaine infusion rates according to therapeutic effectiveness and side-effects.     

Interpretation of middle ear fluid concentrations of antibiotics: comparison between ceftibuten, cefixime and azithromycin

AIMS: The aim of this study was to determine the potential influence of variables such as the cell content in the fluid, and serum levels, on the concentrations of ceftibuten, cefixime and azithromycin in the middle ear fluid of patients suffering from acute otitis media. METHODS: This randomized, open study compared the penetration of ceftibuten (9 mg kg(-1) 18 patients), cefixime (8 mg kg(-1), 16 patients) and azithromycin (10 mg kg(-1) 16 patients) into the intracellular and extracellular compartments of middle ear fluid of 50 paediatric patients (aged 8-14 years) with acute otitis media. Middle ear fluid was extracted by tympanocentesis 4, 12 and 24 h after dosing and divided into two fractions: with cells (as collected) (C+) and cell-free (C-). Antibiotics were assayed in C+ and C- samples by h.p.l.c. RESULTS: Ceftibuten achieved greater penetration into middle ear fluid than cefixime and azithromycin. Higher concentrations of ceftibuten (CTB) and cefixime (CFX) were found in the C- fraction (CTB: 4h 13.3+/-1.86; 12h 4.7+/-1.18; 24h 0.5+/-0.2. CFX: 4h 3.2+/-1.4; 12h 1.5+/-0.5; 24h>(0.1 mgl(-1)) than in the C+ fraction (CTB:4 h 8.4+/-4.3; 12 h 2.88+/-1.19; 24 h 0.3+/-0.27. CFX: 4 h 1.2+/-0.6; 12 h 0.8+/-0.2; 24 h>0.1 mg l(-1)) at the each time point, while the opposite was true for azithromycin (C-: 4 h 0.11+/-0.04; 12 h 0.12+/-0.08; 24 h 0.23+/-0.12. C+: 4 h 0.38+/-0.24; 12 h 0.9+/-0.03; 24 h 1.05+/-0.3 mg l(-1)). CONCLUSIONS: This study demonstrates that the penetration of antibiotics into the middle ear fluid is influenced by its serum concentrations as well as by the cell content in the fluid. Ceftibuten achieved higher middle ear fluid concentrations than cefixime in C+ and C- fractions at all time points. Both ceftibuten and cefixime concentrations are negatively influenced by the cell content in the fluid. In contrast the concentration of azithromycin to the middle ear fluid is positively influenced by the cell content in the fluid.     

Effects of short-term lamotrigine treatment on pharmacokinetics of carbamazepine

AIM AND METHOD: The effects of short-term treatment with lamotrigine (LTG) (100 mg twice daily for one week) on single dose pharmacokinetics of carbamazepine (CBZ, 200 mg) were investigated in a randomized, double-blinded, placebo-controlled cross-over study with 10 healthy volunteers. RESULTS: Pharmacokinetic parameters for CBZ or for CBZ-10,11-epoxide, the main metabolite of CBZ, were not significantly affected by LTG pretreatment. The mean (+/- SEM) elimination half-life of CBZ was 33.0+/-1.8 h after pretreatment with placebo and 30.1+/-2.0 h after a one-week-pretreatment with LTG (NS). The area under the serum concentration curve to infinity (AUC) of CBZ was 638+/-45 micromol/l after placebo and 624+/-53 micromol/l after LTG (NS). Changes in the peak serum concentration, from 9.0+/-0.3 micromol/l to 9.2+/-0.4 micromol/l (LTG), and in the time to peak serum concentration, from 9.3+/-1.1 h to 9.1+/-1.2 h (LTG), were also not significant. CONCLUSION: These data support the earlier findings that LTG does not significantly affect the rate or extent of absorption, or elimination of CBZ.     

Pharmacokinetics of ginsenoside Rg1 in rat medial prefrontal cortex,hippocampus, and lateral ventricle after subcutaneous administration

The present study aimed to investigate pharmacokinetics of Rg1 in rat medial prefrontal cortex (mPFC), hippocampus (HIP), and lateral ventricle (LV) after subcutaneous injection. For the first time, intracerebral pharmacokinetics of Rg1 was studied in freely moving rats by microdialysis technique. Rg1 concentrations in dialysates were detected by a liquid chromatography–tandem mass spectrometry (LC-MS/MS) method and were revised using in vivo probe-recovery in HIP and LV. The pharmacokinetic parameters were then determined using non-compartmental models. Since the in vivo recoveries remained stable in HIP and LV during 9 h dialysis, average recoveries were used to revise dialysate concentrations. After dosing, Rg1 was soon detected in brain extracellular fluid (bECF) and cerebrospinal fluid (CSF). The elimination of Rg1 was significantly slower in mPFC than in HIP and LV, and significantly greater AUC was obtained in mPFC than in HIP. Rg1 kinetics in bECF and CSF indicate that Rg1 can go across the blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCSFB), and then immediately distribute to learning and memory-related regions in brain, which may lead to rapid pharmacological onset. There may be active transport and target-mediated disposition of Rg1 in the CNS, which need to be further clarified.     

Distribution of paclitaxel in plasma and cerebrospinal fluid

Our objective was to assess the distribution of paclitaxel in plasma and cerebrospinal fluid (CSF) in a cancer patient, and evaluate the role of the formulation vehicle Cremophor EL (CrEL) in drug distribution. Analysis of paclitaxel concentrations in CSF was performed using a triple-quadrupole mass spectrometric assay with electrospray ionization. Total and unbound paclitaxel levels in plasma were measured by liquid chromatography and equilibrium dialysis, respectively, and CrEL concentrations were determined by a colorimetric dye-binding microassay. Clinical samples were obtained from a 54-year-old female with breast cancer receiving a weekly regimen of paclitaxel (dose 60 mg/m2). The disposition of total paclitaxel in plasma was characterized by a bi-exponential elimination (terminal half-life 9.17 h) and a total clearance of 19.4 l/h/m2. The fraction of unbound paclitaxel in plasma ranged from 7.6 to 12.4% (unbound drug CL 176 l/h/m2). The plasma clearance of CrEL was 0.332 l/h/m2, whereas CrEL levels were undetectable in CSF (below 0.5 microl/ml). Concentrations of paclitaxel in CSF (range 45.5-162 pg/ml) and unbound CSF:unbound plasma concentration ratios (range 0.093-9.53%) progressively increased up to 24 h, with a mean unbound drug fraction in CSF of 84+/-3.6% (range 81-88%). These findings indicate that there is substantial distribution of paclitaxel to CSF. Since the fraction of unbound paclitaxel is different between plasma and CSF, measurement of unbound paclitaxel is required to accurately assess the extent of drug penetration.     

Pharmacokinetics of fluconazole in serum and cerebrospinal fluid in a patient with AIDS and cryptococcal meningitis

The detailed pharmacokinetics of fluconazole in serum and cerebrospinal fluid (CSF) were studied in a patient with acquired immunodeficiency syndrome and cryptococcal meningitis, after an intravenous dose of 400 mg. Fluconazole exhibited a serum elimination half-life of 34.2 hours, distribution volume of 0.56 L/kg, and clearance of 0.19 ml/min/kg. Peak CSF concentration occurred at 4 hours after the dose. Overall penetration of fluconazole based on the ratio of areas under the curve of CSF to serum was 70%. The drug exhibited an excellent pharmacokinetic profile for treatment of central nervous system fungal infections.     

The plasma and cerebrospinal fluid pharmacokinetics of sorafenib after intravenous administration in non-human primates

Purpose Sorafenib is a small molecule inhibitor of multiple signaling kinases thought to contribute to the pathogenesis of many tumors including brain tumors. Clinical trials with sorafenib in primary and metastatic brain tumors are ongoing. We evaluated the plasma and cerebrospinal fluid (CSF) pharmacokinetics (PK) of sorafenib after an intravenous (IV) dose in a non-human primate (NHP) model. Methods 7.3 mg/kg of sorafenib free base equivalent solubilized in 20% cyclodextrin was administered IV over 1 h to three adult rhesus monkeys. Serial paired plasma and CSF samples were collected over 24 h. Sorafenib was quantified with a validated HPLC/tandem mass spectrometry assay. PK parameters were estimated using non-compartmental methods. CSF penetration was calculated from the AUC_CSF : AUC_plasma. Results Peak plasma concentrations after IV dosing ranged from 3.4 to 7.6 μg/mL. The mean ± standard deviation (SD) area under the plasma concentration from 0 to 24 h was 28 ± 4.3 μg•h/mL, which is comparable to the exposure observed in humans at recommended doses. The mean ± SD clearance was 1.7 ± 0.5 mL/min/kg. The peak CSF concentrations ranged from 0.00045 to 0.00058 μg/mL. The mean ± SD area under the CSF concentration from 0 to 24h was 0.0048 ± 0.0016 μg•h/mL. The mean CSF penetration of sorafenib was 0.02% and 3.4% after correcting for plasma protein binding. Conclusion Sorafenib is well tolerated in NHP and measurable in CSF after an IV dose. The CSF penetration of sorafenib is limited relative to total and free drug exposure in plasma.     

Neuropharmacokinetics of a new alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) modulator, S18986 [(S)-2,3-dihydro-[3,4]cyclopentano-1,2,4-benzothiadiazine-1,1-dioxide], in the rat.

The aim of our study was to determine the neuropharmacokinetics of S18986 [(S)-2,3-dihydro-[3,4]cyclopentano-1,2,4-benzothiadiazine-1,1-dioxide], a new positive allosteric modulator of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid-type receptors, in the rat. We focused on its blood-brain barrier (BBB) uptake and on its brain intra- and extracellular fluid (bICF-bECF) partitioning. BBB transport of S18986 was measured using the in situ brain perfusion technique. bECF concentrations were determined by microdialysis in the two effector areas, i.e., frontal cortex (FC) and dorsal hippocampus (DH), and blood samples were collected simultaneously through a femoral catheter. Cerebrospinal fluid and brain tissue concentrations were determined using a conventional pharmacokinetic approach. Using all the experimental data, pharmacokinetic modeling was applied to describe the S18986 blood-brain disposition. The brain uptake clearance of S18986 was found to be high, about 20 mul s(-1) g(-1). Terminal half-lives were similar in plasma and brain, at around 1 h. Experimental and predicted blood and brain concentrations were a good fit with the pharmacokinetic model, which assumed first-order rate constants at each interface. Ratios of bECF to the unbound plasma area under the curve (AUC) were 0.24 in FC and 0.25 in DH, whereas ratios of bICF/plasma AUC were 1 in FC and 1.5 in DH. We conclude that despite the ratio of bECF/plasma AUC below 1, there is nevertheless an elevated BBB uptake of S18986. This can be explained by the S18986 nonhomogenous bECF/bICF partitioning, since S18986 mainly distributes into hippocampal bICF. This illustrates the importance of taking bECF/bICF partitioning into account when interpreting the neuropharmacokinetics of a drug.     

The pharmacokinetics of isoniazid and hydrazine metabolite in plasma and cerebrospinal fluid of rabbits

The pharmacokinetics of isoniazid (INH) and hydrazine metabolite (HYD) in plasma and cerebrospinal fluid (CSF) of ten rabbits was studied after separate intravenous (i.v.) and oral (p.o.) administration in a crossover study. The concentrations of INH and HYD in the biological fluids were determined by high performance liquid chromatography (HPLC). There was no difference in the area under plasma concentration-time curves, indicating that oral absorption was complete. The mean apparent volume of distribution after i.v. (3.02 +/- 0.55 L) was smaller (p less than 0.01) than that after p.o. (4.29 +/- 1.25 L) dosing. The elimination t1/2 of INH in CSF was longer (p less than 0.005) than that in plasma after either route of administration. There was no significant barrier to the penetration of INH into the CSF from the general circulation. The HYD plasma concentrations were similar after either route. HYD was eliminated at a slower rate (Ke = 0.17 h-1) than INH (Ke = 0.59 h-1). There was prolonged exposure of the body to HYD (greater than 6 h - above 0.1 micrograms/ml).     

Pharmacokinetics of pyrazinamide in plasma and CSF of rabbits following intravenous and oral administration

The pharmacokinetics of pyrazinamide (PZA) in cerebrospinal fluid (CSF) and plasma of 10 rabbits were studied after separate intravenous (i.v.) and oral (p.o.) administration, in a cross-over study. Concentrations of PZA in biological fluids were determined by high performance liquid chromatography (HPLC). After p.o. dose PZA was absorbed rapidly and peak plasma concentration was attained at 0.5 h post administration. After i.v. dose, the plasma PZA concentrations declined rapidly within 10 min and subsequently more slowly following a bi-exponential manner. No difference was observed in the area under plasma concentration-time curves indicating oral absorption was complete and no apparent first-pass metabolism occurred. The (mean +/- S.D.) elimination t1/2 after i.v. (1.04 +/- 0.18 h) was significantly shorter (P less than 0.0005) than that after oral (1.95 +/- 0.63 h) dose and the apparent volume of distribution was also significantly smaller (P less than 0.005) after i.v. (3.211 +/- 0.412 l) than after oral (5.936 +/- 1.607 l) administration. The elimination t1/2 of PZA in CSF was nearly identical to that in plasma after either i.v. (1.07 +/- 0.20 h) or p.o. (1.84 +/- 0.56 h) administration. There is no apparent barrier in rabbits for the penetration of PZA into CSF from the general circulation.