Genetic mapping of the Tsw locus for resistance to the Tospovirus Tomato spotted wilt virus in Capsicum spp. and its relationship to the Sw-5 gene for resistance to the same pathogen in tomato.

The Tsw gene conferring dominant resistance to the Tospovirus Tomato spotted wilt virus (TSWV) in Capsicum spp. has been tagged with a random amplified polymorphic DNA marker and mapped to the distal portion of chromosome 10. No mapped homologues of Sw-5, a phenotypically similar dominant TSWV resistance gene in tomato, map to this region in C. annuum, although a number of Sw-5 homologues are found at corresponding positions in pepper and tomato. The relationship between Tsw and Sw-5 was also examined through genetic studies of TSWV. The capacity of TSWV-A to overcome the Tsw gene in pepper and the Sw-5 gene in tomato maps to different TSWV genome segments. Therefore, despite phenotypic and genetic similarities of resistance in tomato and pepper, we infer that distinct viral gene products control the outcome of infection in plants carrying Sw-5 and Tsw, and that these loci do not appear to share a recent common evolutionary ancestor.

Comparative genetics of disease resistance within the solanaceae.

Genomic positions of phenotypically defined disease resistance genes (R genes) and R gene homologues were analyzed in three solanaceous crop genera, Lycopersicon (tomato), Solanum (potato), and Capsicum (pepper). R genes occurred at corresponding positions in two or more genomes more frequently than expected by chance; however, in only two cases, both involving Phytophthora spp., did genes at corresponding positions have specificity for closely related pathogen taxa. In contrast, resistances to Globodera spp., potato virus Y, tobacco mosaic virus, and tomato spotted wilt virus were mapped in two or more genera and did not occur in corresponding positions. Without exception, pepper homologues of the cloned R genes Sw-5, N, Pto, Prf, and I2 were found in syntenous positions in other solanaceous genomes and in some cases also mapped to additional positions near phenotypically defined solanaceous R genes. This detailed analysis and synthesis of all available data for solanaceous R genes suggests a working hypothesis regarding the evolution of R genes. Specifically, while the taxonomic specificity of host R genes may be evolving rapidly, general functions of R alleles (e.g., initiation of resistance response) may be conserved at homologous loci in related plant genera.

Disposition of recombinant human interleukin-10 in subjects with various degrees of renal function.

The pharmacokinetics of intravenously administered recombinant human interleukin-10 (rHuIL-10) were evaluated in 18 subjects with creatinine clearances (Clcr) between 2.7 and 116.7 mL/min/1.73 m2. Serum samples for rHuIL-10 were obtained over a 48-hour period after a single 25 micrograms/kg i.v. bolus infusion. AUC, total body clearance (Clp), and steady-state volume of distribution (Vdss) were derived by compartmental methods. Analysis of serum concentrations showed statistically significant group differences for log-transformed AUC and original scale Clp (p < 0.01). The AUC and effective half-life increased, while the mean Clp of rHuIL-10 decreased as renal function declined. A linear relationship between AUC and Clcr as well as Clp and Clcr demonstrates that the disposition of rHuIL-10 is altered in subjects with renal insufficiency. No serious adverse events were noted.

The penetration of ceftibuten into the respiratory tract.

STUDY OBJECTIVE: To determine the penetration of ceftibuten into various respiratory tissues and fluids. DESIGN: Single-dose, open-label, pharmacokinetic study. SETTING: Veterans Administration Medical Center. PATIENTS: Twelve hospitalized men aged 34 to 75 years with a variety of noninfectious pulmonary symptoms/diseases. INTERVENTIONS: Patients received a single oral dose of ceftibuten, 200 mg, prior to undergoing diagnostic fiberoptic bronchoscopy. Plasma samples for the determination of ceftibuten concentrations were collected pretreatment and up to 12 h postdosing. Nasal secretions, tracheal secretions, BAL fluid, and lung tissue from a biopsy were obtained at bronchoscopy from 2 to 7 h postdosing. MEASUREMENTS AND RESULTS: Mean pharmacokinetic parameters for ceftibuten in plasma were the following: maximum observed plasma concentration (Cmax), 8.77 microg/mL; time to reach Cmax, 2.2 h; area under the plasma concentration-time curve extraploated to infinity, 49.21 microg/h/mL; and terminal elimination half-life, 3.17 h. These parameters were similar to those obtained in studies using healthy volunteers. Mean penetration of ceftibuten into nasal, tracheal, and bronchial secretions was 47%, 50%, and 30%, respectively. Mean penetration into BAL fluid was 81%, whereas penetration into lung tissue was 39%. No patient experienced any adverse effects related to ceftibuten. CONCLUSIONS: Ceftibuten penetrates well into various tissues and fluids of the upper and lower respiratory tracts. The results support the activity of ceftibuten in the treatment of upper and lower respiratory tract infections.

Renal changes associated with naproxen sodium administration in cynomolgus monkeys.

Naproxen sodium was administered to cynomolgus monkeys (Macaca fascicularis) by oral gavage at daily doses of 44, 88, or 176 mg/kg for 2 wk (2 monkeys/gender) or of 44 mg/kg for 13 wk (4 monkeys/gender). Body weight loss occurred in at least one monkey in all naproxen sodium-dosed groups in the 2-wk (up to 16% loss) and 13-wk (up to 22% loss) studies. Increases in plasma naproxen concentrations were dose proportional between 44 and 88 mg/kg but were less than dose proportional between 88 and 176 mg/kg. Up to 2-fold increases in creatinine and/or serum urea nitrogen values as well as higher renal weights occurred in monkeys receiving 176 mg/kg for 2 wk or 44 mg/kg for 13 wk. Microscopically, renal changes were observed in all naproxen sodium-dosed groups. Renal findings after 2 wk of exposure included increased interstitial ground substance, tubular dilatation, and tubulointerstitial nephritis; in the 13-wk study, cortical tubular atrophy and interstitial fibrosis were also observed. These studies identify the kidney as the target organ of naproxen sodium in cynomolgus monkeys.

Effects of single intravenous doses of recombinant human interleukin-10 on subsets of circulating leukocytes in humans.

Recombinant human interleukin-10 (rhIL-10) is a potent and specific immunomodulatory agent which inhibits endotoxin-stimulated pro-inflammatory cytokine production by monocytes, blocks T-lymphocyte activation by antigen presenting cells, and modulates T(H)1/T(H)2 balance in immune responses. In previous clinical trials, rhIL-10 administered to healthy volunteers induced rapid and transient elevations of neutrophil and monocyte counts and reductions of lymphocyte counts in addition to suppression of endotoxin-stimulated whole blood cytokine synthesis. We sought to better characterize the effects of rhIL-10 on immunophenotypically defined subsets of circulating leukocytes that could be relevant to its immunomodulatory effects. Healthy volunteers were given single doses of 10 microg/kg rhIL-10 (n = 8) or equivalent placebo (n = 4) by intravenous injection. Significant changes of circulating leukocytes included transiently increased neutrophils and monocytes with parallel increases of CD33+ and CD14+ cells. Total lymphocytes as well as total CD3+, CD3+/CD4+ and CD3+/CD8+ cells transiently decreased. Mean fluorescence intensity of CD11a (integrin alpha-chain subunit of lymphocyte function antigen-1, LFA-1) on lymphocytes transiently but significantly decreased, suggesting a mechanism for transient alteration of lymphocyte trafficking. In addition, mean fluorescence intensity of HLA-DR (major histocompatibility class II) on CD14+ cells (predominantly monocytes) transiently but significantly decreased, implying a possible alteration of antigen presenting function. Further study will be required to elucidate the immunomodulatory roles and potential clinical significance of these hematologic changes in therapeutic trials of rhIL-10 in patients with chronic inflammatory and autoimmune diseases.

Pharmacokinetics of flutamide in patients with renal insufficiency.

AIMS: The aim of this study was to determine the pharmacokinetic parameters of flutamide, a nonsteroidal antiandrogenic compound, and its pharmacologically active metabolite, hydroxyflutamide, in renal insufficiency. Haemodialysis (HD) clearance of flutamide and hydroxyflutamide was also determined. METHODS: Pharmacokinetic parameters were assessed for flutamide and hydroxyflutamide in 26 male subjects with normal renal function (creatinine clearance by 24 h urine collection, CLcr, greater than 80 ml min(-1) 1.73 m(-2); n=6) or reduced renal function; CLcr=50-80 (n=7), 30-49 (n=3), 5-29 (n=4), and <5 ml min(-1) 1.73 m(-2)-HD (n=6), following a single, oral 250 mg flutamide dose. Subjects undergoing HD received a second 250 mg dose of flutamide 4 h prior to HD; blood and dialysate were collected during HD to determine dialysability of flutamide and hydroxyflutamide. RESULTS: Cmax, tmax, AUC, t1/2, and renal clearance of flutamide and hydroxyflutamide did not differ between groups. Less than 1% of the dose appeared in dialysate as hydroxyflutamide. No serious adverse events were observed. CONCLUSIONS: Renal function did not affect flutamide nor hydroxyflutamide disposition. HD did not alter hydroxyflutamide pharmacokinetics. Dosing adjustments for renal impairment or HD are not indicated for flutamide.

Pharmacokinetics and leukocyte responses of recombinant human interleukin-10.

PURPOSE: To study the pharmacokinetics and ex vivo leukocyte responses of recombinant human IL-10 (rHuIL-10) following single s.c. and i.v. dosing. METHODS: A randomized two-way cross-over study was undertaken in 17 healthy volunteers in which rHuIL-10 was administered as 25 microg/kg s.c. and i.v. doses. Blood samples were collected for 48 hr after dosing to determine serum IL-10 concentrations. Inhibitory activity of IL-10 on ex vivo production of inflammatory cytokines (TNF-alpha and IL-1beta) by LPS-treated peripheral blood cells were measured over 96 hr. RESULTS: A physiologically-relevant modeling approach was developed to determine the pharmacokinetics for two routes of administration (s.c. and i.v.). The i.v. dose showed polyexponential disposition with CL of 65 mL/kg/hr, Vss of 70 mL/kg, and t1/2 of 1.94 hr. Absolute bioavailability averaged 42% for s.c. dosing which produced lower but sustained concentrations. Substantial and prolonged suppression of TNF-alpha and IL-1beta production was achieved during IL-10 treatment. The Hill Function was used to account for the joint concentration-dependent immunosuppressive action of rHuIL-10 after both i.v. and s.c. doses. The IC50 values were about 0.03 ng/ml and Imax values were about 0.85 for both TNF-alpha and IL-1beta suppression. The degree of change as well as the duration of leukocyte response was greater after s.c. administration than after i.v. administration. CONCLUSION: rHuIL-10 shows favorable PKPD characteristics especially by the s.c. route of administration which produced prolonged suppression of cytokine production (ex vivo) which may be applicable in various immune-related disorders.

Pharmacokinetic drug interaction study: administration of ceftibuten concurrently with the antacid mylanta double- strength liquid or with ranitidine.

This study investigated the influence of antacid (Mylanta Double-Strength Liquid; J & J-Merck Consumer, Fort Washington, PA) and the H2 antagonist ranitidine on the pharmacokinetics of ceftibuten, a once-daily oral cephalosporin. Eighteen male volunteers received, in a randomized, three-way, crossover design, a single oral 400-mg dose of ceftibuten after an overnight fast (1) alone, (2) with antacid (60 mL), and (3) with ranitidine (after 3 days of dosing, 150 mg/12 hours). Serial blood and urine samples were collected during a 24-hour period after each administration, with a 1-week washout between treatments. Ceftibuten, and its metabolite ceftibuten-trans, were analyzed in plasma and urine by high-performance liquid chromatography. Bioavailability parameters, maximum plasma concentration and area under the plasma concentration-time curve to infinity of ceftibuten were unaffected by treatment with antacid. These parameters were somewhat higher when ceftibuten was administered with ranitidine, but they were still within the ranges seen in normal healthy volunteers. The excretion of ceftibuten was independent of treatment. The concentrations of ceftibuten-trans were low in both plasma and urine with all three treatments. It is concluded that the co-administration of antacid and ranitidine are unlikely to affect the bioavailability and antibacterial efficacy of ceftibuten.

Pharmacodynamics of subcutaneous recombinant human interleukin-10 in healthy volunteers.

Interleukin-10 inhibits T-lymphocyte activation and proliferation and lipopolysaccharide-induced monocyte production of proinflammatory cytokines. Fifty-four healthy volunteers received single doses of recombinant human interleukin-10 (1.0, 2.5, 5.0, 10, 25, or 50 micrograms/kg) or placebo by subcutaneous injection (randomized double-blind assignment). Clinical adverse events were infrequent at doses below 50 micrograms/kg (five of six subjects had mild flu-like syndrome). Mean serum interleukin-10 concentrations were dose related. The mean terminal-phase half-life ranged from 2.7 to 4.5 hours, and the apparent volume of distribution ranged from 0.70 to 1.35 L/kg. Hematologic changes included transient mild to moderate increases of neutrophil counts, decreases of lymphocyte counts, and a delayed decrease of platelet counts. Recombinant human interleukin-10 significantly suppressed production of the proinflammatory cytokines interleukin-1 beta and tumor necrosis factor-alpha by whole blood stimulated ex vivo with Escherichia coli lipopolysaccharide.

Pharmacokinetics of isepamicin following a single administration by intravenous infusion or intramuscular injections.

The pharmacokinetics of isepamicin following administration of a 1-g dose were evaluated for 18 healthy male volunteers between the ages of 26 and 38. In a randomized crossover fashion, each volunteer received doses of isepamicin by a 30-min intravenous infusion and as an intramuscular injection. Blood samples were collected at specified times after dosing and assayed for isepamicin by a validated radioimmunoassay method. The individual plasma concentration-time curves were analyzed by noncompartmental methods. In general, the pharmacokinetics after intravenous infusion and intramuscular injection were similar. As expected, the maximum concentration of isepamicin in serum following intramuscular injection (37.2 microg/ml) was lower than the observed concentration at the end of infusion (66.7 microg/ml). The areas under the concentration-time curves from 0 h to infinity following intramuscular and intravenous administration were 164.8 and 154.5 microg x hr/ml, respectively, indicating complete absorption following intramuscular administration. The respective mean terminal-phase half-life (t1/2) values were 2.6 and 3.6 h. Although t1/2 was slightly longer following intravenous infusion, the small difference in the observed t1/2 values was not considered to be clinically significant. Total body clearances following intramuscular injection and intravenous infusion were 1.3 and 1.4 ml/min/kg, respectively, which were similar to renal serum creatinine clearances in healthy volunteers (> 1.14 ml/min/kg). The drug was safe and well tolerated. The results of the present study clearly show complete absorption of isepamicin following intramuscular administration. The similarity in the pharmacokinetics after intravenous infusion and intramuscular dosing would permit interchangeable administration of isepamicin by either route without compromising clinical efficacy.

Pharmacokinetics of intramuscularly administered isepamicin in man.

The pharmacokinetics of isepamicin, a broad-spectrum aminoglycoside antibiotic, was studied in man after intramuscular administration. Two groups each of 6 volunteers received isepamicin for 10 consecutive days by intramuscular injection at respective doses of 7.5 mg/kg once daily or 7.5 mg/kg twice daily. Plasma and urinary concentrations of isepamicin were determined using a specific HPLC method. In both groups, there was no drug accumulation following multiple administration. The t1/2, which ranged from 2.4 to 2.7 h, was independent of the dosage regimen. Isepamicin excreted into (0-24 h) urine accounted for virtually 100% of the dose. The results show that the pharmacokinetics of isepamicin are similar with these dosage regimens. The drug undergoes no detectable biotransformation, does not accumulate upon multiple dosing, and is cleared solely by urinary excretion.

In-vivo/in-vitro correlation of four extended release formulations of pseudoephedrine sulfate.

An in-vivo/in-vitro correlation was established for four formulations of pseudoephedrine sulfate modified release tablets exhibiting different in-vivo and in-vitro release rate and absorption characteristics. In-vitro release rate data were obtained for 12 individual tablets of each formulation using the USP Apparatus 2 paddle stirrer at 50 rev min-1 in 1000 ml 0.1 N hydrochloric acid for the first hour followed by 0.1 M phosphate buffer at pH 7.5 for hours 2-16. Inspection of the individual and mean release rate data indicated that the in-vitro release rate of pseudoephedrine sulfate was consistent with the intended design of the four extended release formulations. The in-vivo bioavailability and pharmacokinetics of these formulations were evaluated in 20 healthy volunteers under fasted conditions. Wagner-Nelson analyses of the in-vivo data revealed extended release absorption profiles for all four formulations. Linear regression analyses of the mean percentage of dose absorbed versus the mean in-vitro release resulted in statistically significant correlations (r2 > 0.99, p < 0.0001) for each formulation. Qualitative rank order correlations were observed among all combinations of in-vivo and in-vitro parameters. These data support a Level A correlation between in-vivo absorption profiles and in-vitro release rates of four pseudoephedrine sulfate extended release formulations determined in fasted healthy volunteers.

Pharmacokinetics of loratadine and pseudoephedrine following single and multiple doses of once- versus twice-daily combination tablet formulations in healthy adult males.

The pharmacokinetic profiles of single and multiple doses of loratadine, descarboethoxyloratadine (DCL) (the major active metabolite of loratadine), and pseudoephedrine were determined in a randomized, open-label, two-way crossover study in 24 healthy men. Subjects received a single dose (day 1) and multiple doses (days 3 to 10) of a once-daily (QD) formulation of loratadine 10 mg in an immediate-release coating and pseudoephedrine sulfate 240 mg in an extended-release core (CLAR-ITIN-D 24 HOUR tablets), and a twice-daily (BID) formulation of loratadine 5 mg in an immediate-release coating and pseudoephedrine sulfate 120 mg, with 60 mg in an immediate-release coating and 60 mg in the barrier-protected core (CLARITIN-D 12 HOUR tablets) in study sessions, each separated by a 10-day washout period. Both regimens were safe and well tolerated. On day 1, plasma loratadine, DCL, and pseudoephedrine concentrations were higher following the QD formulation than following the BID formulation, as expected. On day 10, loratadine and DCL maximum plasma concentration (Cmax) values were, on average, 87% and 35% higher, respectively, for the QD formulation than for the BID formulation; however, the values of the area under the plasma concentration-time curve from 0 to 24 hours (AUC0-24) for loratadine and DCL were equivalent (90% confidence interval [CI]: 83% to 110% for loratadine; 90% to 107% for DCL). On day 10, pseudoephedrine Cmax and AUC0-24 values were equivalent (90% CI for Cmax: 94% to 109%; for AUC: 91% to 106%) for the two formulations, and lower pseudoephedrine concentrations were observed from 16 to 24 hours with the QD formulation. Both loratadine/pseudoephedrine formulations produced equivalent loratadine and DCL AUC0-24 values and equivalent pseudoephedrine Cmax and AUC0-24 values following multiple dosing. The lower pseudoephedrine concentrations in the evening with the QD formulation may minimize the potential for insomnia in patients when compared with the BID formulation.

Single-dose pharmacokinetics of isepamicin in young and geriatric volunteers.

Isepamicin is a new aminoglycoside antibiotic with activity against both gram-negative and gram-positive bacteria. The pharmacokinetics of isepamicin were evaluated after a 0.5-hour intravenous infusion of alpha 15-mg/kg dose to groups of young adults and geriatric volunteers. Isepamicin was safe and well tolerated. No adverse events related to the infusion were reported. As age increased, there were increases in the elimination phase half-life (t1/2 beta) and the area under the plasma concentration-time curve extrapolated to infinity (AUC0-infinity), and decreases in systemic (Cl) and renal clearance (Clr). The changes seen in Cl with age were a result of changes in renal function estimated by creatinine clearance (Clcr). There were no apparent correlations between age and maximum plasma concentration (Cmax), half-life of the tau-phase (t1/2 tau), volume of distribution at steady-state (Vdss), or the amount of isepamicin excreted in urine within 24 hours after dose administration (Ae24 hrs). When comparing the elderly (61-80 years old) with the younger (21-60 years) volunteers, the (AUC0-infinity), and t1/2 beta values were higher in the elderly and the Cl and Clr values were lower, but Cmax, t1/2 tau and Vdss were similar in the two age groups. The contribution of the tau-phase to the overall AUC was minimal and similar for the two age groups. Also, there were no gender effects on the pharmacokinetics of isepamicin in both the young and elderly volunteers. These results demonstrate that changes in the pharmacokinetics of isepamicin in the elderly are attributable to changes in renal function, whereas age, per se, is not a significant factor.

Characterization of tryptophan synthase alpha subunit mutants of Arabidopsis thaliana.

Three mutations in the Arabidopsis thaliana gene encoding the alpha subunit of tryptophan synthase were isolated by selection for resistance to 5-methylanthranilate or 5-fluoroindole, toxic analogs of tryptophan pathway intermediates. Plants homozygous for trp3-1 and trp3-2 are light-conditional tryptophan auxotrophs, while trp3-100 is a more leaky mutant. Genetic complementation crosses demonstrated that the three mutations are allelic to each other, and define a new complementation group. All three mutants have decreased steady-state levels of tryptophan synthase alpha protein, and the trp3-100 polypeptide exhibits altered electrophoretic mobility. All three mutations were shown to be in the TSA1 (tryptophan synthase alpha subunit) structural gene by several criteria. Firstly, the trp3-1 mutation is linked to TSA1 on the bottom of chromosome 3. Secondly, the trp3-1 mutation was complemented when transformed with the wild-type TSA1 gene. Finally, DNA sequence analysis of the TSA1 gene revealed a single transition mutation in each trp3 mutant.

Comparative bioavailability of ceftibuten in capsule and suspension forms.

The comparative bioavailability of ceftibuten, a new third-generation cephalosporin antibiotic given orally once daily, in capsule and suspension dosage forms, was assessed in healthy male subjects. In three separate studies, subjects received either a 400-mg dose as a suspension or one laboratory-batch, 400-mg capsule; one laboratory-batch, 400-mg capsule or two laboratory-batch, 200-mg capsules; or one production-batch, 400-mg capsule or two laboratory-batch, 200-mg capsules. Plasma samples were assayed for ceftibuten using high-performance liquid chromatography, and the data were assessed using pharmacokinetic and statistical methods. Confidence intervals for the maximum plasma concentration and the area under the plasma concentration-time curve extrapolated to infinity were within 80% to 125% of guidelines, demonstrating the bioequivalence of the two treatments within each of the three studies. One 400-mg capsule (laboratory or production batch) was bioequivalent to two 200-mg capsules used in a clinical efficacy trial; the 400-mg suspension was bioequivalent to a 400-mg capsule (laboratory batch). Thus we concluded that the capsule and the suspension dosage forms were bioequivalent.

Clinical, hematologic, and immunologic effects of interleukin-10 in humans.

We conducted a double-blind, placebo-controlled study to investigate the safety, pharmacokinetics, and immunological properties of interleukin-10 (IL-10) administration in healthy humans. Volunteers received a single intravenous bolus injection of recombinant human IL-10 (1, 10, or 25 micrograms/kg) or placebo. Cytokine production in whole blood and peripheral blood mononuclear cells (PBMC) was assessed before and 3, 6, 24, and 48 hr after the injection. Peak serum concentrations of IL-10 (15 +/- 1.1, 208 +/- 20.1, and 505 +/- 22.3 ng/ml) occurred after 2-5 min for 1, 10, and 25 micrograms/kg IL-10, respectively. The terminal-phase half-life was 3.18 hr. A transient leukocytosis (24-63% above baseline) was observed 6 hr after injection, which coincided with a dose-dependent decrease (12-24%) in neutrophil superoxide generation. There was a marked inhibition (60-95%) of endotoxin-induced IL-6 production from whole blood in each group receiving IL-10. Production of IL-8 in endotoxin-stimulated blood was reduced in the 10 micrograms/kg group. In PBMC stimulated with phytohemagglutinin and phorbol ester, there was a decrease (72-87%) in interferon-gamma (IFN gamma) production 6 hr after IL-10 with a return to pre-IL-10 levels after 24 hr. This reduction was only partially associated with a decrease in the number of CD2-bearing cells. We conclude that IL-10 administration into humans is without significant side effects, and a single injection reduces ex vivo production of IL-6, IL-8, and IFN gamma.

Effect of Felbamate on The Pharmacokinetics of Clonazepam.

To assess the possible interaction between clonazepam and felbamate, a double-blind, randomized, placebo-controlled, two-way crossover study was conducted in 18 healthy male volunteers. Volunteers were administered clonazepam (1 mg q12h) and felbamate (1200 mg q12h) or matching placebo for 10 days during each period of the crossover. Following morning dosing on day 10, blood samples were obtained over 12 h for the determination of clonazepam and the metabolites 7-amino-clonazepam and 7-acetamido-clonazepam. Felbamate increased clonazepam's C(max) and AUC(0--12 h) by 17% and 14%, respectively (p < 0.01). The 90% confidence intervals following log-transformation for each of these pharmacokinetic parameters were within the generally accepted interval (80--125%) for bioequivalence. Felbamate had no significant effect on the pharmacokinetics of 7-amino-clonazepam, whereas 7-acetamido-clonazepam concentrations were below the limit of quantification in all but one subject. Adverse events were mainly central nervous system in nature, with a greater incidence reported during coadministration with felbamate compared with placebo. Overall, felbamate appears to have no clinically relevant effects on the pharmacokinetics of clonazepam.

Effect of felbamate on valproic acid disposition in healthy volunteers: inhibition of beta-oxidation.

We assessed the effects of felbamate (FBM) on the disposition of valpr oic acid (VPA) in healthy volunteer men. Eighteen subjects received sodium VPA, 400 mg/day for 21 days. Plasma and urine samples were taken on day 7 to document the steady-state disposition of VPA alone. From day 8 to day 21, subjects received placebo or FBM at the following doses (mg/day): 1,200, 2,400, 3,000, or 3,600 (n = 2-4 per group). Many adverse events (AE) occurred from about day 10; 2 subjects dropped out and 1 continued on a reduced FBM dose. Pharmacokinetic studies were repeated on day 21 for the 16 subjects who completed the study. FBM was measured in plasma and urine by high-performance liquid chromatography (HPLC). VPA and its 2-en, 4-en, and 3-oxo metabolites in plasma, and VPA (nonconjugated and total), and its 3-oxo and 4-hydroxy metabolites in urine were measured by gas chromatography/mass spectrometry (GC/MS). Mean plasma FBM trough concentrations on day 21 ranged from 26.9 mu g/ml (1,200 mg dose) to 76.8 mu g/ml (3,600-mg dose). Mean plasma VPA C max values were 32-42 mu g/ml in the various subgroups when VPA only was administered. Higher plasma VPA levels were observed when FBM was administered concurrently (55.4-63.8 mu g/ml). The excretion of 3-oxo-VPA in urine was significantly lower on day 21 than on day 7, whereas VPA-glucuronide was significantly increased. The effects of FBM on VPA disposition were dose dependent and were maximal at approximately 2400 mg/day. FBM has caused significant inhibition of the beta-oxidation pathway for VPA metabolic clearance, and this had been largely compensated by increased VPA glucuronidation.