Pharmacokinetics and tolerability of eslicarbazepine acetate and oxcarbazepine at steady state in healthy volunteers.

PURPOSE: Investigate the pharmacokinetics of once-daily (QD; 900 mg) and twice-daily (BID; 450 mg) regimens of eslicarbazepine acetate (ESL) and BID (450 mg) regimen of oxcarbazepine (OXC) at steady state in healthy volunteers. METHODS: Single-center, open-label, randomized, three-way (n = 12) crossover studies in healthy volunteers. KEY FINDINGS: Mean eslicarbazepine Cmax,ss (in µm) following ESL QD (87.3) was 33.3% higher (p < 0.05) compared to ESL BID (65.5) and 82.1% higher (p < 0.05) compared to OXC BID (48.0). The mean area under the curve (AUC)ss,0-τ (in µmol h/L) following the last dose of an 8-day repeated dosing was 1156.3, 1117.6, and 968.4 for ESL QD, ESL BID, and OXC BID, respectively. The ratio eslicarbazepine plasma exposure (µmol h/L) to ESL daily-dose (µmol) was 0.381 (1156.3:3037.3), 0.368 (1117.6:3037.3), and 0.271 (968.4:3567.6) for ESL-QD, ESL-BID, and OXC-BID, respectively, which translates into a 40.6% increase in the ability of ESL-QD compared to OXC-BID to deliver into the plasma their major active entity eslicarbazepine. The extent of plasma exposure to ESL minor metabolites: (R)-licarbazepine and oxcarbazepine after ESL-QD was 71.5% and 61.1% lower, respectively, than after OXC-BID. Twenty, 24 and 38 treatment emergent adverse events were reported with ESL-QD, ESL-BID, and OXC-BID, respectively. SIGNIFICANCE: ESL-QD resulted in 33.3% higher peak plasma concentration (Cmax,ss ) of eslicarbazepine and similar extent of plasma exposure (AUCss,0-τ ) when compared to ESL-BID, which may contribute to the efficacy profile reported with once-daily ESL. In comparison to OXC-BID, administration of ESL-QD resulted in 40.6% increase in the delivery of eslicarbazepine into the plasma as well as a significantly lower systemic exposure to (R)-licarbazepine and oxcarbazepine.

Three-phase hollow fiber microextraction based on two immiscible organic solvents for determination of tricyclic antidepressant drugs: comparison with conventional three-phase hollow fiber microextraction.

The aim of this research was to compare the extraction efficiencies of two modes of three-phase hollow fiber microextraction (HF-LLLME) based on aqueous and organic acceptor phases for analysis of tricyclic antidepressant (TCA) drugs. High-performance liquid chromatography with photodiode array detection (HPLC-DAD) was applied for determination of the drugs. In order to examine the ability of the new concept of HF-LLLME based on organic acceptor solvent in comparison with aqueous acceptor phase to extract the analytes, four TCAs were selected. The effect of different extraction conditions (i.e., type of acceptor phase, hollow fiber length, ionic strength, stirring rate, and extraction time) on the extraction efficiency of the TCAs was investigated and optimized using central composite design (CCD) as a powerful tool. Both methods were characterized by good linearity and high repeatability, but HF-LLLME with organic acceptor provided higher extraction efficiency and thus lower limits of detection (LODs). Calibration curves were linear (r(2)>0.996) in the range of 0.2-200 µgL(-1). LODs for all the TCAs ranged from 0.08 to 0.2 µgL(-1) using HPLC-DAD. Also an improvement in sensitivity of several orders of magnitude was achieved using single-ion monitoring GC-MS analyses (0.04 µgL(-1)) due to compatibility of this technique with GC instrument. The applicability of the proposed HF-LLLME/GC-MS and HPLC-DAD methods was demonstrated by analyzing the drugs in spiked urine and plasma samples. The obtained recoveries of the drugs in the range of 87.9-109.2% indicated the excellent capability of the developed method for extraction of TCAs from complex matrices.

Improvement and validation the method using dispersive liquid-liquid microextraction with in situ derivatization followed by gas chromatography-mass spectrometry for determination of tricyclic antidepressants in human urine samples.

A simple, rapid and sensitive method termed dispersive liquid-liquid microextraction (DLLME) combined with gas chromatography-mass spectrometry (GC/MS) was developed for the determination of tricyclic antidepressants (TCAs) in human urine sample. An appropriate mixture of methanol (disperser solvent), carbon tetrachloride (extraction solvent), and acetic anhydride (derivatization reagent) was injected rapidly into human urine sample. After extraction, the sedimented phase was analyzed by GC/MS. The calibration curves obtained with human urine were linear with a correlation coefficient of over 0.99 in the range of 2.0/5.0-100 ng mL(-1). Under the optimum conditions (carbon tetrachloride: 10 µL, methanol: 150 µL), the detection limits and the quantification limits of the tricyclic antidepressants were 0.5-2.0 ng mL(-1) and 2.0-5.0 ng mL(-1), respectively. The average recoveries of TCAs were 88.2-104.3%. Moreover, the inter- and intra-day precision and accuracy was acceptable at all concentrations. The results showed that DLLME is applicable to the determination of trace amounts of TCAs in human urine sample.

Effect of renal impairment on the pharmacokinetics of eslicarbazepine acetate.

OBJECTIVE: Antiepileptic drugs are often used in patients with some degree of renal impairment. The objective of this study was to evaluate the effect of renal function on the pharmacokinetics of eslicarbazepine acetate (ESL, formerly known as BIA 2-093), a new antiepileptic drug under clinical development. METHODS: ESL pharmacokinetics following 800 mg single dose was characterized in subjects with normal renal function (n=8, control group), and in patients with mild renal impairment (n=8), moderate renal impairment (n=8), severe renal impairment (n=8), and end-stage renal disease requiring hemodialysis (n=8). RESULTS: ESL suffered extensive first-pass hydrolysis to eslicarbazepine (S-licarbazepine), the main active metabolite. While eslicarbazepine Cmax did not significantly differ between the different groups, the extent of systemic exposure, assessed by AUC, increased when renal function decreased. Eslicarbazepine CL/F and CLR were, respectively, 3.40 l/h and 1.04 l/h (17.3 ml/min) in the control group, and 2.10 l/h (35.0 ml/min) and 0.61 l/h (10.2 ml/min) in the mild, 1.60 l/h (26.7 ml/min) and 0.22 l/h (3.7 ml/min) in the moderate, and 1.33 l/h (21.2 ml/min) and 0.09 l/h (1.5 ml/min) in the severe renal impairment groups. Although the total amount of eslicarbazepine recovered in urine until 72 h post-dose was similar in the control and mild renal impairment groups, a decrease was found in the moderate and severe renal impairment groups. Major metabolites recovered in urine were eslicarbazepine and its glucuronide form. Clearance of minor metabolites (R-licarbazepine, oxcarbazepine and their glucuronides) was also dependent on renal function. In patients with end-stage renal disease, dialysis was effective in removing the ESL metabolites from the circulation. CONCLUSIONS: ESL metabolites are excreted primarily by renal route and their clearance is dependent on renal function. ESL dosage adjustment may be necessary in patients with a creatinine clearance <60 ml/min.

Safety, tolerability, and pharmacokinetic profile of BIA 2-093, a novel putative antiepileptic, in a rising multiple-dose study in young healthy humans.

This was a double-blind, randomized, placebo-controlled study to investigate rising oral doses of BIA 2-093 (S-(-)-10-acetoxy-10,11-dihydro-5H-dibenz/b,f/azepine-5-carboxamide), a putative new antiepileptic drug. Within each of 4 dosage groups of 8 healthy male adult subjects, 2 subjects were randomized to receive placebo, and the remaining 6 subjects were randomized to receive BIA 2-093 (200 mg bid, 400 mg qd, 800 mg qd, and 1200 mg qd) for 8 days. Concentrations of BIA 2-093 in plasma or urine were generally not measurable. Median maximum plasma concentrations of the major metabolite (licarbazepine, (+/-)-10,11-dihydro-10-hydroxy-5H-dibenz/b,f/azepine-5-carboxamide) were attained (t(max)) at 2 to 3 h postdose; thereafter, plasma concentrations declined with a mean apparent terminal half-life of 9 to 13 h following repeated dosing. The extent of systemic exposure to licarbazepine increased in an approximately dose-proportional manner following single and repeated administration. Licarbazepine accumulated in plasma following repeated administration of BIA 2-093; the mean extent of accumulation (R(O), calculated from AUC(0-tau) (day 8)/AUC(0-tau) (day 1)) was 3.0 after repeated, twice-daily dosing and 1.4 to 1.7 after once-daily dosing. Steady-state plasma licarbazepine concentrations were attained at 4 to 5 days of once- or twice-daily dosing, consistent with an effective half-life on the order of 20 to 24 h. The mean renal clearance of licarbazepine from plasma was approximately 20 to 30 mL/min, which is low compared with the glomerular filtration rate. The total amount of licarbazepine recovered in urine was approximately 20% within 12 h postdose and 40% within 24 h postdose. All adverse events were mild in severity, except for 1 case of somnolence of moderate severity, which occurred in a subject receiving 1200 mg BIA 2-093. The incidence of adverse events was similar between all treatment groups, including placebo. There were no serious adverse events. In conclusion, BIA 2-093 was well tolerated and appeared to be rapidly and extensively metabolized to licarbazepine following single and repeated administration to healthy young subjects.

Detection of 2-hydroxyiminostilbene in the urine of patients taking carbamazepine and its oxidation to a reactive iminoquinone intermediate.

Carbamazepine is one of the most widely used anticonvulsants in North America; however, its use is associated with a range of serious idiosyncratic adverse reactions. These reactions are thought to result from the formation of chemically reactive metabolites. Carbamazepine is extensively metabolized in the liver and one of the major metabolites is 2-hydroxycarbamazepine, which has previously been detected as a urinary metabolite excreted by rats and humans along with its further metabolized product, 2-hydroxyiminostilbene. In this study, we found that the urine of patients taking carbamazepine appeared to contain more of the glucuronide of 2-hydroxyiminostilbene than that of 2-hydroxycarbamazepine. We have also demonstrated that 2-hydroxyiminostilbene can be oxidized readily to an iminoquinone species by HOCl, H2O2 or even on exposure to air. The reactivity of this iminoquinone as an electrophile was studied. It was shown to react with sulfhydryl-containing nucleophiles, such as glutathione and N-acetylcysteine. We also found a metabolite with the same molecular weight as 4-methylthio-2-hydroxyiminostilbene, but not the corresponding carbamazepine derivative, in the urine of patients taking carbamazepine and this presumably reflects the formation of a glutathione conjugate of the reactive iminoquinone. This iminoquinone intermediate may play a role in carbamazepine-induced idiosyncratic reactions.

Pharmacokinetics of the antiarrhythmic agent tiracizine: steady state kinetics in comparison with single-dose kinetics.

Serum and urine kinetics of unchanged tiracizine (T), a new class I antiarrhythmic agent, and three metabolites (M1, 2, and 3) were assessed in eight healthy extensive metabolizers after a single oral administration of 50 mg tiracizine and during steady state (50 mg b.i.d.). Additionally, tiracizine-induced ECG changes were measured. Considerable accumulation of M1 and M2 was observed during repeated dosing (M1, Cmax,ss = 391.8 ng mL-1 against Cmax,sd = 132.8 ng mL-1; M2, Cmax,ss = 143.2 ng mL-1 against Cmax,sd = 25.8 ng mL-1). However, significant increases of AUC (AUC tau = 261.9 ng h mL-1 against AUC0-infinity,sd = 182.9 ng h mL-1), Cmax (Cmax,ss = 75.9 ng mL-1 against Cmax,sd = 56.9 ng mL-1) and t 1/2 beta (t 1/2 beta,ss = 4.0 h against t 1/2 beta,sd = 2.4 h) of the parent compound indicate non-linear kinetics. The significant decrease in renal clearance of all four substances as well as the decrease of non-renal tiracizine clearance with repeated dosing led to the assumption that non-linearity is due to saturable renal excretion and a fall in intrinsic tiracizine clearance. PQ time was prolonged significantly during steady state and culminated at the tmax of the parent compound, whereas there was no change in any ECG parameter after a single-dose administration of 50 mg tiracizine.

Day-night variations in the renal excretion of the antiarrhythmic agent tiracizine and its metabolites.

Daytime and nighttime urinary recovery as well as morning and evening trough serum levels of the antiarrhythmic agent tiracizine and three of its metabolites (M1, M2, and M3) were assessed during a 7-day multiple-dose study period (50 mg tiracizine twice daily) in eight healthy volunteers. A significantly lower mean steady-state urinary recovery was observed during the daytime as compared with during the nighttime (Ae (tot tau d)=42.0 +/- 15.7% vs. Ae (tot tau n)=51.2 +/- 19.6%). This difference is mainly due to a substantial increase of M1 and a smaller increase of M2 urinary recovery by night. Results of additional in vitro investigations showed the ratio of the nonionic/ionic forms of M1 and M2 to be highly dependent on pH in the range of pH 5-pH 7. Therefore, the observed day-night variations might be attributed to alterations of ionization, i.e., nonionic tubular reabsorption of the metabolites due to circadian differences in urinary pH. Trough serum levels of M1 and M2 tended to be higher at 7 P.M. as compared with 7 A.M. Due to the narrow therapeutic index of class I antiarrhythmics, the present results indicate the need for further investigations concerning the effect of urinary pH on the pharmacokinetics of tiracizine and its metabolites.

The biliary and renal elimination of the new muscarinic-1-antagonist AWD 26-06 in volunteers with T-tube after cholecystectomy.

The biliary and renal elimination of the new muscarinic-1-antagonist AWD 26-06 were investigated in 6 female volunteers (age: 26-69 years) 9-14 days after cholecystectomy and T-tube construction. After a single oral dose of 50 mg AWD 26-06 as an aqueous solution the amount of the unchanged substance was determined in serum, T-tube bile and urine with a special HPLC-method. The concentration maximum was reached earlier and higher in bile (60 +/- 22 min; 10.8 +/- 5.7 micrograms/ml) than in serum (73 +/- 28 min; 0.98 +/- 0.53 micrograms/ml). During the whole observation time of 24 h the AWD 26-06 concentration in bile was 2-21-fold higher than in serum. In mean 2.3 +/- 1.5% of the administered dose were eliminated unchanged by bile and 12.2 +/- 5.9% by urine. More than 70% of the dose were metabolized. The results gave a hint at active liver transport processes and an enterohepatic recirculation. A drug interaction was observed with valproic acid on the metabolic level. The great interindividual variability of pharmacokinetic data can be caused by the heterogeneity of the subject group and a genetic polymorphism in the metabolism of AWD 26-06. The bile sampling by means of a T-tube is a simple but effective method under consideration of special conditions.

[Biotransformation and pharmacokinetics of AWD 26-06, 8-chloro-5,10-dihydro-5-[bis(2-hydroxyethyl)aminoacetyl]-11H-dibenzo[d, c][1,4]diazepin-11-one hydrochloride in the rat]. / Biotransformation und Pharmakokinetik von AWD 26-06, 8-Chlor-5,10-dihydro-5-[bis(2-hydroxyethyl)aminoacetyl]-11H- dibenzo[d,c][1,4]diazepin-11-on-hydrochlorid an der Ratte.

After p.o. administration to rats AWD 26-06 (1) is rapidly but incompletely absorbed. The relatively short distribution (t1/2 alpha = 37 min) is followed by a middle-long elimination (t1/2 beta = 14 h). The volumen of distribution do not suggest an uncommon accumulation in deep compartments. About 70% of 1 were excreted unchanged with the feces. In urine and feces 18 metabolites were identified. The structure of 10 products could be elucidated. All metabolites have changed side-chains. Furthermore, the tricyclic molecule without side-chain and a N-methyl derivative were identified. The metabolites with so far unknown structure contain the unsubstituted tricyclic moiety too.

[Biotransformation and pharmacokinetics of AWD 26-06, 8-chloro- 5,10-dihydro-5-[bis(2-hydroxyethyl)aminoacetyl]-11H-dibenzo[b,c] [1,4]diazepin-11-one hydrochloride, in the rat]. / Pharmakokinetik von AWD 26-06, 8-Chlor-5,10-dihydro-5-[bis(2- hydroxyethyl)aminoacetyl]-11H-dibenzo[b,e][1,4]diazepin-11-on- hydrochlorid an der Ratte.

Following p.o. and i.v. application of the 14C-labelled AWD 26-06 (6 mg/kg b.w.) with anticholinergic activity, blood levels (-24 h) and excretion (urine, feces-72 h; bile-7 h) were studied in Wistar rats. Intestinal absorption amounted to 30% of the dose administered in water solution. Elimination half-lives in blood were 0.6 h and (after Cmax 3-4 h p.a.) 8 h. Excretion was mainly by feces (unchanged drug and biliary excreted metabolites) and to less extent by urine.

[The metabolism of bonnecor]. / Metabolizm bonnekora.

Bonnecor metabolism in the rat urine was studied. The main metabolites of bonnecor were identified by means of chromatography-mass-spectrometry.

Pharmacokinetic study of iminodibenzyl antipsychotic drugs, clocapramine and Y-516 in dog and man.

The pharmacokinetic properties of the iminodibenzyl antipsychotic drugs clocapramine (CCP, 3-chloro-5-[3-(4-carbamoyl-4-piperidino piperidino) propyl]-10, 11-dihydro-5H-dibenzo[b, f]azepine) and Y-516 (3-chloro-5-[3-(2-oxo-1, 2, 3, 5, 6, 7, 8, 8a-octahydroimidazo [1,2-a] pyridine-3-spiro-4'-piperidino) propyl]-10, 11-dihydro-5H-dibenzo[b, f]azepine) were investigated in dog and man. Dogs were administered CCP and Y-516 intravenously, intraperitoneally, and orally, and the concentrations of the parent drugs and their metabolites in the plasma and urine were determined. Half-life (t1/2) was approximately the same by all three administration routes, being approximately 5 h for CCP and 3 h for Y-516. Bioavailability following oral administration was 0.16 +/- 0.01 (mean +/- SD, n = 3) for CCP and 0.29 +/- 0.07 for Y-516. The fractions of dose absorbed following oral administration were 0.43 +/- 0.07 and 0.79 +/- 0.24, and the fractions of dose metabolized in the liver due to the first-pass effect were 0.63 +/- 0.05 and 0.63 +/- 0.04 for CCP and Y-516, respectively. Y-516 was detected in the plasma after intraperitoneal and oral administration of CCP. The ratio of the AUC of Y-516 to that of CCP was 0.06 following intraperitoneal administration and 0.40 following oral administration. This indicated that while the metabolism of CCP into Y-516 may occur partly in the liver due to the first-pass effect, it occurs mostly within the gastrointestinal tract itself or its mucosa.(ABSTRACT TRUNCATED AT 250 WORDS)

A carpipramine related fatality.

A fatality following ingestion of the tricyclic antidepressant carpipramine (Prazinil) and ethyl alcohol is described. Carpipramine was quantitated by high performance liquid chromatography. The concentration of carpipramine was 2.0 mg/L in blood and 0.44 mg/L in urine. Ethyl alcohol was measured by headspace gas chromatography and found to be 105 mg/dL in blood and 55 mg/dL in the urine. Quantitative analysis of stomach contents was positive for carpipramine by thin-layer chromatography. To our knowledge, this is the first reported fatality involving carpipramine.

[Pharmacokinetics and metabolism of 3-carbethoxyamino-5-dimethylamino-acetyl-iminodibenzyl hydrochloride (Bonnecor, AWD 19-166, GS 015) in the rat]. / Pharmakokinetik und Metabolisierung von 3-Carbethoxyamino-5-dimethylamino-acetyl-iminodibenzyl-hydrochlorid (Bonnecor, AWD 19-166, GS 015) an der Ratte.

Excretion, blood level, distribution, and metabolite samples were studied on the rat after application of GS 015 marked by 14C. The compound is quickly and completely absorbed and metabolized from an aqueous solution. The marked substances form a broad blood level maximum, at the occasion of which a main metabolite distinguishes itself apart from the initial compound at first provable yet. The elimination half-life from the blood is 6 h. An intense influx of radioactive substance into the tissues takes place. The excretion of the marked metabolites occurs mainly renally making appear a second main metabolite. Striking sex differences are partly observed in the parameters tested.

The metabolism of mianserin in women, rabbits, and rats: identification of the major urinary metabolites.

The biotransformation of orally administered 3H-mianserin was investigated in female human subjects, rabbits, and rats by identification of the major urinary metabolites. Three days after dosing, the urinary excretion of radioactivity was 53% in women, 36% in rats, and 80% in rabbits. In the women's urine, 15% of the administered dose was excreted in the form of mianserin (conjugated plus nonconjugated); in the animal species this quantity was 1-2%. Mianserin was predominantly metabolized to 8-hydroxy analogs in all species; in rats, 8-hydroxydesmethylmianserin was the principal metabolite. Demethylation was an important metabolic pathway in the animal species, but not in women. Novel N-formyl compounds were detected in the urine of both animal species, but the possibility that these were artifacts formed during extraction with chloroform cannot be ruled out. Trace amounts of two compounds in which the piperazine moiety of mianserin was absent, 11H-dibenz[b,e]azepine and 11 H-dibenz[b,e]azepine-2-ol, were identified in the urine of rabbits and rats, respectively.

In vivo studied on the metabolism of dibenzo [c,f]-[1,2] diazepine.

The in vivo metabolism of dibenzo [c,f]-[1,2] diazepine (I) was studied after i.p. administration to rats, in order to observe the influence of the heteroatom on the metabolic pathway. Metabolites were separated by chromatography and their structures elucidated by mass spectrometry, by both gas chromatography coupled with mass spectrometry and the direct inlet system. Six metabolites were identified, some of them by direct comparison with authentic samples.