Carbamazepine-nefazodone interaction in healthy subjects.

The pharmacokinetic interaction between nefazodone and carbamazepine was investigated in 12 healthy male volunteers. Subjects received nefazodone 200 mg twice daily for 5 days, and blood sample collection was performed on day 5 for 0- to 48-hour pharmacokinetic analysis. A 4-day wash-out phase then followed from days 6 to 9. Carbamazepine 200 mg was administered once daily from days 10 to 12, and then 200 mg was given twice daily from days 13 to 44. A 0- to 48-hour pharmacokinetic analysis was performed on day 38. Nefazodone 200 mg twice daily was added to the dosing regimen from days 40 to 44, and a subsequent 0- to 48-hour pharmacokinetic analysis was performed on day 44. Coadministration of nefazodone increased steady-state plasma area under the concentration-time curve (AUC) of carbamazepine from 60.77 (+/-8.44) to 74.98 (+/-12.88) microg x hr/mL (p < 0.001) and decreased the active carbamazepine-10,11-epoxide metabolite AUC concentration from 7.10 (+/-1.16) to 5.71 (+/-0.52) microg x hr/mL (p < 0.005). During the combination, the steady-state AUC of nefazodone decreased from 7,326 (+/-3,768) to 542 (+/-191) ng x hr/mL, and the AUCs of its metabolites (hydroxynefazodone, meta-chlorophenylpiperazine, and triazoledione) decreased significantly as well (p < 0.001). Coadministration of nefazodone 200 mg twice daily and carbamazepine 200 mg twice daily was found to be safe and well tolerated; however, the increased plasma exposure to carbamazepine may warrant monitoring of plasma carbamazepine concentrations with the combination. However, higher doses (>400 mg/day) of carbamazepine could yield more extensive induction, affecting tolerability of the combination. No change in the initial nefazodone dose is necessary, and subsequent dose adjustments should be made on the basis of clinical effects; however, the repercussion of carbamazepine induction of nefazodone metabolism on the antidepressant efficacy has yet to be studied.

Pharmacokinetic evaluation of co-administration of nefazodone and lithium in healthy subjects.

OBJECTIVES: To evaluate the possible pharmacokinetic interaction between nefazodone and lithium. METHODS: Twelve healthy volunteers received nefazodone 200 mg b.i.d. for 5 days. A 4-day washout phase followed from day 6 to day 9. From day 10 to day 20, escalating doses of lithium 250 mg b.i.d. to 500 mg b.i.d. were given; the daily dose of 1000 mg was obtained on day 13. From day 16 to day 20, nefazodone 200 mg b.i.d. was added to the lithium dosing regimen. Venous blood sampling was performed on days 5, 15 and 20 for 0- to 48-h-pharmacokinetic analysis. Nefazodone and its metabolites, hydroxynefazodone, mCPP and triazoledione were assayed by high-performance liquid chromatography (HPLC). Lithium was assayed by flame photometry. RESULTS: Co-administration of nefazodone did not modify pharmacokinetic parameters of lithium at steady-state. Comparison of the area under the plasma or serum concentration-versus-time curve calculated from 0-12 h (AUC0-12) of nefazodone and hydroxynefazodone revealed no significant differences when nefazodone was administered alone or with lithium. The mean maximum peak plasma concentration Cmax and AUC0-12 of meta-chlorophenyl-piperazine (mCPP) were significantly reduced by 27% (P < 0.001) and 16% (P < 0.001) with the co-administration. The mean Cmax and AUC0-12 of triazoledione were reduced by 23% (P < 0.005) and 16% (P < 0.01) by the co-administration. CONCLUSION: Since there were no clinically significant changes in the pharmacokinetics of the parent compounds or metabolites, and the combination was well tolerated, no dosage adjustments of nefazodone or lithium are necessary when they are co-administered.

The kinetic profiles of amlodipine and of a sustained release form of diltiazem.

This study in normotensive subjects compared plasma concentrations of amlodipine (5 mg) and of a sustained release form of diltiazem (300 mg) after single and multiple oral dosings of the two drugs. As a consequence of the galenic form of administered formulations, plasma concentration of diltiazem versus time curves exhibited two peaks corresponding to fast and slow releases of diltiazem. Conversely, the curves of amlodipine plasma concentration depicted only one peak. There was less variability in plasma concentrations and in pharmacokinetics with amlodipine than with diltiazem after both single and multiple oral dosings of the two drugs. These results suggested that amlodipine displayed less variability in blood pressure response at steady-state. The rate of decrease in plasma levels of diltiazem between 24 and 48 hours post-dose was higher than that of amlodipine. So, even after a missed dose, there is only a small decline in plasma concentrations of amlodipine and therefore it suggests a small repercussion on the blood pressure attenuation.

Quantitative measurement of BN50727 in human plasma and urine by combined liquid chromatography/negative ion chemical ionization mass spectrometry using a particle beam interface.

A new sensitive assay has been developed for the quantitative measurement of BN50727 at the picomole level in human plasma and urine. The drug and the internal standard (BN50788) were measured by combined liquid chromatography/negative ion chemical ionization mass spectrometry with methane as the reagent gas. A simple solid-liquid extraction procedure was used to isolate BN50727 from the complex biological matrices. The mass spectrometer was tuned to monitor the intense and stable ion at m/z 333 which was generated in the ion source by a dissociative capture process. This assay was performed with 1 ml of plasma or 0.1 ml of urine and the quantification limit of the method was statistically calculated as 1 ng ml-1. The very low relative standard deviations and mean percentages of error calculated during the different within-day or between-day repeatability assays have clearly demonstrated the ruggedness of the technique for the routine determination of BN50727 in biological fluids. Some preliminary results on the pharmacokinetics of the drug are presented to illustrate the applicability of this powerful liquid chromatographic/mass spectrometric method.

Quantitative measurement of 4-hydroxy tamoxifen in human plasma and mammary tumours by combined gas chromatography/negative chemical ionization mass spectrometry.

A highly sensitive and specific assay was developed for the quantitative measurement of 4-hydroxy tamoxifen (4-OH Tam) at the femtomole level in human plasma and mammary tumours. The drug and deuterated internal standard (4-OH Tam D4) were measured by gas chromatography/negative chemical ionization mass spectrometry with methane as the reactant gas. The two compounds of interest were isolated from the complex biological matrices using a solid-phase extraction procedure with Extrelut 1 columns. Soft operating conditions were required to convert 4-OH Tam to the fluorinated derivatives with pentafluorobenzyl chloride. The mass spectrometer was tuned to monitor the abundant and stable molecular ions at m/z 581 and 585 which were generated in the ion source by an electron capture process. This assay required only 0.5 ml of plasma or 0.5 g of mammary tissue, and the quantification limits of the method were 20 pg ml-1 for the body fluids or 100 pg g-1 for the tissue samples. The very low relative standard deviation and mean percentage error calculated during the different within-day or day-to-day repeatability assays have clearly demonstrated the ruggedness of the technique for routine analysis of 4-OH Tam.

Pharmacokinetics of quinine and doxycycline in patients with acute falciparum malaria: a study in Africa.

The pharmacokinetics of quinine was investigated in patients with acute falciparum malaria treated with quinine alone or in the presence of doxycycline. Twenty-six patients divided into two groups of equal number were enrolled in the study. In the absence of doxycycline, the volume of distribution of quinine (mean +/- SD) was estimated to be 1.32 +/- 0.32 L/kg, and its clearance was 0.125 +/- 0.47 L/h/kg, which was only in partial agreement with previously published data. No effect of doxycycline on the pharmacokinetics of quinine was observed.

Simultaneous determination of beclomethasone, beclomethasone monopropionate and beclomethasone dipropionate in biological fluids using a particle beam interface for combining liquid chromatography with negative-ion chemical ionization mass spectrometry.

A new simple and sensitive assay has been developed for the simultaneous quantitative measurement of beclomethasone dipropionate and its hydrolysis products in human plasma and urine. Beclomethasone 17.21-dipropionate, beclomethasone 17-monopropionate, beclomethasone and the internal standard, dexamethasone 21-acetate, were measured by combined liquid chromatography and negative-ion chemical ionization mass spectrometry with methane as the reagent gas. A particle beam interface from Hewlett Packard was used. Under mild operating conditions, abundant and stable characteristic high-mass ions were generated in the ion source of the mass spectrometer by a resonance electron-capture mechanism. The fast extraction procedure requires 1 ml of plasma or urine, and the quantification limit of the method is 1 ng ml-1 for the three tested compounds.

Lack of effect of ponsinomycin on the pharmacokinetics of nicoumalone enantiomers.

Pharmacokinetic interaction between ponsinomycin-nicoumalone was studied in six subjects who received an 8 mg oral dose of racemic nicoumalone alone and 4 days into an oral regimen of ponsinomycin 800 mg twice daily. The concentrations of R(+) and S(-)-nicoumalone in plasma were measured using a stereospecific h.p.l.c. assay. The disposition characteristics of nicoumalone enantiomers in the control phase of this study were similar to those reported previously with the exception of the data for one subject whose oral clearance for S(-)-nicoumalone was seven times lower than those in the other subjects. A statistically significant effect of ponsinomycin on the kinetics of R(+) and S(-)-nicoumalone was not demonstrated.

A rapid and highly sensitive method for the quantitative determination of dexamethasone in plasma, synovial fluid and tissues by combined gas chromatography/negative ion chemical ionization mass spectrometry.

A new, simple and highly sensitive assay is developed for the quantitative measurement of very low levels of dexamethasone in human plasma, synovial fluid and tissues following a topical administration of the drug. Dexamethasone and the internal standard, flumethasone, are measured by gas chromatography/negative ion chemical ionization mass spectrometry with methane as the reagent gas. After a three-step extraction procedure, the two compounds of interest are converted to their trimethylsilyl ether derivatives using trimethylsilylimidazole and formamide as the base catalyst. Under soft derivatization conditions only one chromatographic peak corresponding to the trisubstituted derivative is observed. The mass spectrometer is focused to monitor abundant and stable characteristic high-mass ions (m/z 446 and 464) which are generated in the ion source by an electron capture process. This assay requires only 1 ml of plasma or 0.5 ml of synovial fluid and the detection limit of the method is equal to 0.1 ng ml-1 with a relative standard deviation lower than 6%.

[Pharmacokinetics of ponsinomycine with repeated ingestion in healthy volunteers]. / Pharmacocinétique de la ponsinomycine administrée en prises répétées chez le volontaire sain.

Ponsinomycin or miocamycin (MOM) is a new macrolide which is totally metabolized in vivo. The disposition of its 3 major metabolites (Mb12, Mb6 and Mb9a), was investigated following multiple dosing with ponsinomycin at a dose of 800 mg every 12 h, for 8 days, in healthy volunteers. Drug measurements were conducted by high performance liquid chromatography. In agreement with the low values of their apparent elimination half-lives, respectively less than 1.5 h and 3.0 h, metabolites Mb12 and Mb9a did not accumulate with time. Their pharmacokinetics was apparently stable with time. Conversely Mb6 did accumulate, by approximatively a factor 2, although its apparent elimination half-life was only close to 2 h. This value must therefore be considered with caution. A dose dependency effect was previously observed, Mb6 pharmacokinetics could be non linear with time as well. The relative importance of this metabolite is therefore greater at steady-state, following multiple administration than after single dosing with ponsinomycin.

Effect of ponsinomycin on single-dose kinetics and metabolism of carbamazepine.

The effect of ponsinomycin (or miocamycin), a new macrolide antibiotic, was investigated on the pharmacokinetics of carbamazepine (CBZ) administered as a single dose in healthy volunteers. Disposition of the active 10,11 epoxycarbamazepine (ECBZ) was investigated as well. For each compound both total and free plasma concentrations were measured. A moderate (+13%) but statistically significant (p less than 0.05) increase of CBZ total area under the curve (AUC), was observed in the presence of ponsinomycin, accompanied by a 26% decrease (p less than 0.01) in the AUC of its metabolite. There was a tendency toward an increase in AUC of unbound CBZ, although it was not statistically significant. Together these data suggest that formation of ECBZ is inhibited in the presence of ponsinomycin. The relative importance of the epoxy-diol metabolic pathway being increased at steady state due to autoinduction, results of this study suggest that CBZ plasma levels should be carefully monitored in patients receiving ponsinomycin.

Effect of ponsinomycin on cyclosporin pharmacokinetics.

The influence of treatment with ponsinomycin, a new macrolide antibiotic, on the pharmacokinetics of cyclosporin A has been studied in 10 renal transplant patients. The pharmacokinetics of cyclosporin A was investigated at steady state, before and during treatment with ponsinomycin. On average, the blood levels of cyclosporin A were doubled by the macrolide, possibly due to a decrease in elimination or/and to an increase in absorption. Ponsinomycin should be use very carefully in patients treated with cyclosporin A.