Pharmacokinetics of a single oral dose of baclofen in pediatric patients with gastroesophageal reflux disease.

Transient relaxation of the lower esophageal sphincter (TLESR) is the predominant mechanism of gastroesophageal reflux (GER) in adults and children. Baclofen [4-amino-3-(p-chlorophenyl)-butanoic acid], a gamma-aminobutyric acid (GABA)-B receptor agonist used for the management of spasticity, has been recently shown to significantly inhibit GER in healthy adults without any relevant side effects. The objective of this study was to evaluate the pharmacokinetics of baclofen in a pediatric population with GER disease. In an open-label single-dose pharmacokinetic study, eight children with the diagnosis of GER made on clinical grounds received an oral dose of baclofen, 2.5 mg. Blood samples were drawn from an indwelling venous catheter, and urine was collected during a postdose period of 8 hours. The concentration of baclofen in these body fluids was determined using a validated high-performance liquid chromatography (HPLC) method with electrochemical detection after OPA-sulfite derivatization. Pharmacokinetic data were analyzed using the nonlinear regression program Scientist. Serum concentration-time curves could be best described using a two-compartment open model with a lag time. Mean plasma clearance (Cl) was 315.9 mL/h/kg; volume of distribution (Vd) was 2.58 L/kg; and half-life (T(1/2)beta) was 5.10 hours. No side effects were noted. As half-lives were comparable with those found in adult studies, the risk for accumulation seems not greater in children than in adults. Body composition can have a strong influence on the Vd of baclofen and, therefore, on the dose needed to obtain therapeutic plasma levels. Dosing according to clearly defined age groups with the help of therapeutic drug monitoring seems preferable. In view of the negative correlation between body weight and Vd, dosing according to body weight using adult pharmacokinetic data does not seem an effective way for using baclofen in children.

Effect of grapefruit juice or cimetidine coadministration on albendazole bioavailability.

The assumed metabolic breakdown of albendazole by mucosal CYP3A4 enzymes was studied by coadministering albendazole (10 mg/kg) with grapefruit juice. Concentrations of albendazole sulfoxide (ABZSX), the active metabolite of albendazole, were compared with those after albendazole was administered with water, a fatty meal, or grapefruit juice plus cimetidine (10 mg/kg). In comparison to water, maximum ABZSX concentration (Cmax) was enhanced 6.5-fold by a fatty meal (from 0.24 +/- 0.09 mg/l to 1.55 +/- 0.30 mg/l; mean +/- SD; P < 0.001) and 3.2-fold by grapefruit juice (from 0.24 +/- 0.09 mg/l to 0.76 +/- 0.37 mg/L; P = 0.031). When grapefruit juice was combined with cimetidine, Cmax was significantly lower than with grapefruit juice alone (0.41 +/- 0.29 mg/l and 0.76 +/- 0.37 mg/l, respectively; P = 0.022). The area under the concentration-time curve from 0 to infinity (AUC(0-omega)) followed a comparable pattern. Half-life (T(1/2)) was 8.8 +/- 4.2 hr and 8.2 +/- 4.3 hr after administration with water or a fatty meal (P = 1.000). Grapefruit juice shortened T(1/2) by 46% (P = 0.026). We hypothesize that albendazole is metabolized by CYP3A4 enzymes in the intestinal mucosa. This process can be inhibited by grapefruit juice. Cimetidine decreased albendazole bioavailability.

Effect of dose increase or cimetidine co-administration on albendazole bioavailability.

The low bioavailability of albendazole affects the therapeutic response in patients with echinococcosis. Cimetidine co-administration is reported to improve bioavailability. To analyze the assumed dose-dependent bioavailability of albendazole, we administered 5 to 30 mg/kg albendazole to 6 male volunteers in a randomized cross-over study. To assess the effect of cimetidine (10 mg/kg twice daily), the drug was given with albendazole (20 mg/kg). A dose-dependent bioavailability was not observed. This was due to inter-individual variability of the maximal concentration (Cmax 38%-72%) of albendazole sulphoxide (ABZSX), the active metabolite of albendazole. Cmax was 0.21+/-0.14 mg/L after 5 mg/kg and 0.39+/-0.19 mg/L after 30 mg/kg albendazole (P = 0.217). Cimetidine tended to decrease Cmax by 52% (P = 0.109) and significantly inhibited ABZSX breakdown as indicated by the prolongation of ABZSX elimination half-life from 7.4+/-3.3 hr to 19.0+/-11.7 hr (P = 0.028). Remarkably, the inter-individual variability of Cmax was significantly lower during cimetidine co-administration: 14% versus 72%.

Pharmacokinetic/pharmacodynamic modelling of the eosinopenic and hypokalemic effects of formoterol and theophylline combination in healthy men.

Interactions of formoterol and theophylline were evaluated with the use of pharmacokinetic-pharmacodynamic (PK/PD) modelling. Oral doses of 144 microg of formoterol and 375 mg of theophylline were given separately or combined to healthy subjects. As effect parameters, plasma eosinophil and potassium concentrations were used. Kinetic interactions between formoterol and theophylline were not found. Plasma drug concentrations were linked to the observed effects via an effect compartment model with a sigmoid E max model. The E max values+/-SD for the hypokalemic effects were 2.29+/-0.78 mmol/l for formoterol and 1.64+/-1.16 mmol/l for theophylline (P>0.05). The E max values for the eosinopenic effects were fixed at zero. The EC 50 values of the eosinopenic and hypokalemic effects were respectively 91.4+/-38.2 pg/ml and 128.4+/-52.9 pg/ml for formoterol, and 11. 9+/-4.6 microg/ml and 15.5+/-4.8 microg/ml for theophylline. Effects of both drugs combined were described with a non-competitive interaction model. The correlation coefficients of the fits of the eosinopenic and hypokalemic effects were respectively 0.9520+/-0. 0311 and 0.9371+/-0.0227, supporting our hypothesis of non-competitive interaction.

Simultaneous determination of fentanyl and midazolam using high-performance liquid chromatography with ultraviolet detection.

When measuring fentanyl and midazolam simultaneously in the same plasma sample with standard high-performance liquid chromatography-ultraviolet (HPLC-UV) detection, overlap of the fentanyl peak by the midazolam peak occurs, which makes fentanyl determination impossible. We tested the hypothesis that by acidifying the methanol mobile phase with 0.02% perchloric acid, 70%, it would be possible to separate both peaks. The UV detector was set at 200 nm. Calibration curves for fentanyl (range 0-2000 pg/ml) and midazolam (range 0-400 ng/ml) were linear (r>0.99). The detection limits were 200 pg/ml (fentanyl) and 10 ng/ml (midazolam). Precision and accuracy for intra- and inter-assay variability as well as in-line validation with quality control samples (QCS) were acceptable (<15 and 20%, respectively), except for fentanyl QCS of 200 pg/ml (17.8% precision). Although less sensitive than gas chromatography-mass spectrometry (GC-MS), reliable measurements of fentanyl, simultaneously with midazolam, can be performed with this HPLC-UV system.

Validation of an improved reversed-phase high-performance liquid chromatography assay with reductive electrochemical detection for the determination of artemisinin derivatives in man.

For the determination of artemisinin (ART) and analogs, a reversed-phase high-performance liquid chromatography method using reductive electrochemical detection (ED) was set up with some important modifications as compared to previously published assays. A different technique of deoxygenating resulted in a factor 2-3 lower background current. A Spectroflow 400 liquid chromatograph in combination with a Triathlon autoinjector coupled to a Decade electrochemical detector was used. The detector was operated in the reductive mode as a closed system under chromatography grade helium to exclude any access of oxygen. The Decade has a glassy carbon electrode and a reference Ag/AgCl electrode. Infrequent electropolishing was required implicating a very stable system. By increasing acetonitril or lowering the pH of the mobile phase, the various derivatives could be determined in the same chromatogram. The assay was validated using artemether (ATM) and dihydroartemisinin (DHA) as test substances. In the concentration range seen in people after usual doses (5 to 220 ng/ml), the assay performs with adequate accuracy and precision. The interassay and intraassay precision are < 6% for ATM. For DHA, the interassay and intraassay precision are < 9%. The accuracy expressed as the deviation from the expected concentration varies from -1% to +4.5% for the intraassay ATM-determinations and from +1% to +6.3% for the interassay measurements. For DHA, the accuracy is somewhat less, varying from -0.3% to -9.5% for the intraassay measurements and -0.6% to +2.6% for the interassay measurements. The reproducibility of the assay, measured over a time period of 3 months, is good for ATM and DHA with an interassay precision of < 18% in 70 repetitive samples and an accuracy varying from -0.6% to +7.6%. In a cross-check with two other reference laboratories who used comparable methods of determination, a strong correlation (correlation coefficient > 0.98) was achieved. The method was applied in a study in which artemether was administered orally to healthy white subjects. We consider high-performance liquid chromatography with electrochemical detection an accurate and precise method for quantitative determination of artemisinin derivatives in pharmacokinetic studies.

Determination of enantiomers of bupivacaine in serum using an on-line coupled three column liquid chromatographic system.

An on-line coupled HPLC system is described for the determination of the enantiomers of bupivacaine in serum. The method involves three steps: (i) pre-concentration and clean-up; (ii) the determination of the racemates on a reversed-phase column; and (iii) the separation of the racemates, heart-cut from the reversed-phase column, on an alpha-glycoprotein column. The method is suitable to determine the enantiomers in serum down to 0.1 micrograms ml-1 and can be fully automated. The bupivacaine time course of patients will be shown.