Modification of aflatoxin B1 and ochratoxin A toxicokinetics in rats administered a yeast cell wall preparation.

The cell wall of Saccharomyces cerevisiae can bind mycotoxins in vitro, but there is scarce information on whether this property decreases the absorption of mycotoxins in vivo. The effect of a yeast cell wall preparation (YCW) on toxicokinetics and balance excretion (urine and faeces) of aflatoxin B(1) (AFB1) and ochratoxin A (OTA) was tested in rats after oral administration of each toxin. The (3)H-labelled mycotoxins were used at low doses. Co-administration of YCW with AFB1 decreased the extent, but not the rate, of absorption. Concurrently, radioactivity excreted in faeces increased by up to 55% when compared with controls, whilst the excretion in urine decreased (p < 0.05). The effect of YCW on OTA was less marked, although it increased radioactivity excretion in faeces (up to 16%; p < 0.05) it did not result in changes in urine and toxicokinetic parameters. The in vivo effect is in agreement with the reported in vitro binding ability for these toxins (AFB1 > OTA). In conclusion, these results indicate that YCW could be used to protect monogastric animals against exposure to low dietary levels of selected mycotoxins.

Cefepime in intensive care unit patients: validation of a population pharmacokinetic approach and influence of covariables.

AIM: The purpose of our study was to define and validate a population-pharmacokinetic model including the influence of patients' characteristics on the pharmacokinetics of cefepime. PATIENTS AND METHODS: A total of 55 patients were randomized in Group 1 (34 patients, 320 cefepime concentrations) for the model building and Group 2 (21 patients, 196 cefepime concentrations) for the validation group. They received cefepime as 2 g A 2 or as 4 g continuously. The population pharmacokinetic analysis was carried out using NONMEM and a baseline model was constructed for studying the influence of demographic and biological variables. The model was then validated by a comparison of the predicted and observed concentrations in Group 2. A final model was elaborated from the whole population. RESULTS: Total clearance (CL) was significantly correlated with the serum creatinine (CREA) and the central volume of distribution (V1) was correlated with the body weight (WT). The final model was: CL = 7.14 + (-0.0133 A CREA). V1 = (-16.8) + (0.475 A WT). Q (intercompartmental clearance) = 10.5. V2 = 18.1. The mean pharmacokinetic parameters and their individual variability were: CL (8.24 l/h, 45%), V1 (20.89 l, 60%), V2 (17.95 l, 49%), total volume (38.85 l, 42%) and Q (10.56 l/h, 9%). The bias (1.07 mg/l, IC 95% = -40.46 -+42.60), precision (21.19%) and AFE (1.15) demonstrated the performance of the model. CONCLUSION: We have developed and validated a pharmacokinetic model to estimate cefepime concentrations. We showed that serum creatinine and body weight are factors that may influence the standard dose of cefepime. Our model enabled us to predict cefepime concentrations in other patients.

Pharmacokinetics of ceftazidime and cefepime in burn patients: the importance of age and creatinine clearance.

AIM: The standard dosage recommendations for beta-lactam antibiotics can result in very low drug levels in intensive care (IC) patients and burn patients in the absence of renal dysfunction. We studied the pharmacokinetic parameters and serum concentrations of ceftazidime (CF) and cefepime (CE) in burn patients and analyzed the modifications according to clinical and biological parameters and in particular age and creatinine clearance. MATERIAL AND METHODS: Two pharmacokinetic studies were carried out with daily doses of 1 g x 6 for CF (n = 17) and 2 g x 3 for CE (n = 13). Creatinine clearance (CL(CR)) was both estimated and measured. Blood was sampled at steady state after an initial and a subsequent antibiotic dose. C(max) (maximal) and C(min) (minimal) concentrations were measured by HPLC. The influence of clinical and biological data was analyzed using ANOVA, ANCOVA and stepwise multiple linear regression. RESULTS: The ratio of C(min) to the low MIC break point (4 mg/l) was lower than 4 in 52% of subjects receiving CF and in 80% of subjects receiving CE. The C(min) of CF was correlated with measured CL(CR) and was higher in mechanically ventilated patients than in non-ventilated patients. The clearance of CF was correlated with age. The C(min) of CE was correlated with age and drug clearance with measured CL(CR). Therefore dosage adjustment of these drugs in burn patients needs to take into account age, measured creatinine clearance and the danger of low concentrations occurring when the creatinine clearance is greater than 120 ml x min(-1). CONCLUSION: In burn patients, the pharmacokinetic disposition of CF and CE was much more variable than in healthy subjects. Age and CL(CR) were predictors of the disposition of these antibiotics. Shortening the dosage interval or using continuous infusions will prevent low serum levels and keep trough levels above the MIC for longer periods of time. In view of the lack of a bedside measurement technique for ceftazidime and cefepime levels, we suggest a more frequent use of measured CL(CR) in order to attain efficacious clinical concentrations.

Intermittent administration of ceftazidime to burns patients: influence of glomerular filtration.

OBJECTIVE: The pharmacokinetics of ceftazidime, the antibiotic of choice for treating acute P. aeruginosa infections, may be modified in burns patients. The aim of this study was to identify the factors causing variations in the serum antibiotic concentrations in bums patients. METHODS: 30 patients with serious burns were randomly divided into two groups. Group 1 received a dose of ceftazidime of 2 x 3 g/24 hours. The second group received the same dose but divided into 6 administrations. Blood samples were taken at 24 (M1) and 48 hours (M2) after the start of treatment and the peak and trough serum concentrations of ceftazidime measured by HPLC. Depending on the results, frequency and/or dose was modified to obtain trough concentrations (Cmin) equal to 16 mg/l, i.e. 4 times the MIC. Either the same dose was maintained, but mostly divided up, or it was increased to 1 g x 8 administrations or it was decreased to 1 g x 4 or 1 g x 3. The serum concentrations of ceftazidime obtained were analyzed taking into account the characteristics of the burns patients (multivariate correlation). RESULTS: From the first sample (M1) Cmin was lower than the target concentration in 50% of the patients in Group 1 and 20% in Group 2. The modification of the dosing regimen put into place after the first analysis, led to the patients being further divided into four groups before the second blood sampling. Finally, 5 patients ended up in Group 1. In all patients and for all administration times, a negative correlation was found between Cmin and the creatinine clearance, calculated by using Cockcroft's formula. CONCLUSION: This study highlights the peculiarities of ceftazidime pharmacokinetics seen in burns patients with high interindividual variability. Based on Cmin monitoring and a predefined therapeutic range, dose adjustment was often required. Ceftazidime clearance is correlated with creatinine clearance (Cockcroft's formula), suggesting that this parameter could be used for a priori or a posteriori dose individualization. To respect the summary of the product characteristics (SPC) and reduce the variability in trough concentrations, the dose should be fractionated (1 g x 6) over a 24-hour period or even given as a continuous infusion. Trough concentrations must be evaluated to adapt the dosage regimen to attain target concentrations of 4 x the MIC.

Assessment of renal function in clinical practice at the bedside of burn patients.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: * In burn patients it has been shown ([2]), that there is a correlation between the creatinine clearance (CL(CR)) and the clearance of inulin. * The CL(CR) has never been studied in burn patients who have normal serum creatinine. * The Robert, Kirkpatrick and sMDRD formulae have never been evaluated in burn patients. WHAT THIS STUDY ADDS: * Despite burn patients having normal serum creatinine concentrations, the study showed that there are large variations in CL(CR) which cannot be detected by single serum creatinine measurements, and which have important implications for drug therapy. * It showed that the formulae currently used to calculate creatinine clearance on the basis of serum creatinine are inadequate for use in burn patients, and they should be abandoned in favour of direct measurement from a 24 h urine collection. AIMS: The aim of this study was to evaluate whether the renal function of burn patients could be correctly assessed using a single serum creatinine measurement, within normal limits, and three prediction equations of glomerular filtration taking into account, serum creatinine, age, weight and sex. METHODS: This was a prospective study comprising 36 adult burn patients with a serum creatinine <120 micromol l(-1), within the second or third week following the burn injury. Renal function was assessed using serum creatinine, 24 h urinary CL(CR), and the Cockcroft-Gault, Robert, Kirkpatrick and simplified MDRD equations. RESULTS: Despite normal serum creatinine concentrations in all patients, a significant number had a decreased CL(CR). The urinary CL(CR) was <80 ml(-1) min(-1) 1.73 m(-2) in nine patients (25%), and <60 ml(-1) min(-1) 1.73 m(-2) in five patients (14%). Between the groups having a CL(CR) lower or greater than 80 ml(-1) min(-1) 1.73 m(-2) there were no differences in gender, burn indices, percentage of mechanically ventilated patients or length of hospital stay, but a difference in age. The highest CL(CR) (>140 ml(-1) min(-1) 1.73 m(-2)) was found in 13 patients younger than 40 years. Regression analysis, residual and Bland-Altman plots revealed that neither the Cockcroft-Gault, Robert, Kirkpatrick nor sMDRD equations were specific enough for the assessment of renal function. CONCLUSIONS: In burn patients with normal serum creatinine during the hypermetabolic phase, serum creatinine and creatine based predictive equations are imprecise in assessing renal function.

Increased amikacin dosage requirements in burn patients receiving a once-daily regimen.

Altered pharmacokinetics in burn patients may affect antibiotic plasma concentrations. Typical once-daily dosing (ODD) of 15 mg/kg amikacin (AMK) in burn patients does not always produce peak concentrations (C(max)) reaching the therapeutic objective of six to eight times the minimal inhibitory concentration (MIC). We recorded plasma concentrations following administration of 20 mg/kg AMK in burn patients and studied factors affecting pharmacokinetics. Mean C(max) was 48.3+/-10.8 mg/L and the C(max)/MIC ratio was 6+/-1.35. Statistical analysis demonstrated a relationship between C(max) and the area of the burn and Unit Burn Standard, and between AMK clearance and creatinine clearance (Cl(CR)). We conclude that ODD regimens of AMK in patients with burns >15% body surface area and/or with Cl(CR) >120 mL/min could require doses >20 mg/kg to reach adequate C(max). In all cases, patient therapeutic drug monitoring is essential to ensure the safe usage of these dosing recommendations.

Validation of a liquid chromatography-mass spectrometry method to assess the metabolism of bupropion in rat everted gut sacs.

We have developed a rapid, sensitive and selective LC-MS method for the simultaneous assay of bupropion and its metabolite hydroxybupropion during its intestinal absorption, studied with the rat everted gut sac model. The method was validated in the concentration range of 1-15 microM (0.024-3.58 microg/mL) for bupropion and 0.005-1 microM (0.00127-0.25 microg/mL) for hydroxybupropion with 10 microL injected. Bupropion is used as a probe for the activity of the CYP2B6 isoenzyme of the P450 family of enzymes in man. Its major metabolite hydroxybupropion was found in the serosal media of the gut sac showing that the isoenzyme of the 2B group was active in the intestinal mucosa and metabolized bupropion during its passage across the mucosa. The metabolite was also quantified in the mucosal media indicating its ability to cross the apical membrane of the epithelial cells.

Cefepime in critically ill patients: continuous infusion vs. an intermittent dosing regimen.

The aim of this study was to compare the pharmacokinetic and pharmacodynamic parameters of a continuous infusion of cefepime vs. an intermittent regimen in critically ill adult patients with Gram-negative bacilli infection. The prospective randomized parallel study was carried out in 50 patients with severe pneumonia (n = 41) or bacteremia (n = 9). They received cefepime 4 g/d either as a continuous infusion or intermittent administration 2 x 2 g in combination with amikacin. Patient characteristics and the minimal inhibitory concentration (MIC) of the isolated bacteria were comparable. Clinical outcomes were assessed along with pharmacodynamic indices and compared in both groups (chi2 and Mann-Whitney U-tests). Mechanical ventilation, clinical outcome and bacteriological eradication did not significantly differ between the two groups. Also, the area under the plasma cefepime concentration curve at steady state (AUCss: 612 +/- 369 vs. 623 +/- 319 mg x 1(-1) x h), AUCss > MIC (595 +/- 364 vs. 606 +/- 316 mg x 1(-1) x h) and the area under the inhibitory concentration curve (AUICss: 4258 +/- 5819 vs. 5194 +/- 7465 mg x 1(-1) x h) were similar. If the time above MIC (t > MIC) was not significantly higher in Group 1 (100 +/- 0%) than in Group 2 (90 +/- 11%), t > five-fold MIC in Group 1 (100 +/- 0%) was significantly higher (p < 0.01) than in Group 2 (82 +/- 25%). The mean time over the French breakpoint (4 mg/l) was 100 +/- 0% and 72 +/- 27% in Group 1 and 2 (p < 0.001), respectively. In contrast to intermittent cefepime administration, continuous infusion of cefepime consistently maintained a serum concentration > 5 x the MIC of typical Gram-negative nosocomial pathogens. This results in greater bactericidal activity against organisms with a higher (2 mg/l) cefepime breakpoint even if the clinical outcome is not significantly modified.

Validation of a liquid chromatography-mass spectrometry method to assess the metabolism of dextromethorphan in rat everted gut sacs.

A rapid, sensitive and selective liquid chromatography-mass spectrometry (LC-MS) method was developed for the simultaneous assay of dextromethorphan and its metabolites in tissue culture medium and its intestinal metabolism studied with the rat everted gut sac model. The method was validated in the concentration range of 0.1-2.5 microM (27.1 ng/mL-0.677 microg/mL) for dextromethorphan and 0.005-0.5 microM for dextrorphan and 3-methoxymorphinan (1.28 ng/mL-0.128 microg/mL) and 3-hydroxymorphinan (1.22 ng/mL-0.122 microg/mL). The limits of quantification (LOQ) were 0.0025 microM (12.5 fmoles, 3.4 pg, 5 microL injected) for dextromethorphan; 0.0025 microM for dextrorphan, 3-methoxymorphinan (24.9 fmoles, 6.4 pg injected), and 3-hydroxymorphinan (25.1 fmoles, 6.1 pg injected) with 10 microL injected. The detection of dextrorphan and 3-methoxymorphinan showed that both the P450 isoforms CYP3A and 2D were active in the intestinal mucosa and metabolised dextromethorphan during its passage across the mucosa.

Liquid chromatographic-mass spectrometric method to assess cytochrome P450-mediated metabolism of testosterone by rat everted gut sacs.

A rapid, sensitive and specific method was developed for the simultaneous assay of testosterone, androstenedione and 6beta-hydroxytestosterone (6beta-OHT) in the TC199 tissue culture medium used in intestinal drug metabolism studies with the rat everted gut sac model. An electrospray LC-MS method was validated in the concentration range of 0.025-9.5 microM (7.2 ng-2.7 microg/mL) for testosterone and androstenedione and 0.01-4 microM (3 ng-1.2 microg/mL) for 6beta-hydroxytestosterone. The limits of quantification (LOQ) with an injection volume of 10 microL were 0.0005 microM (4.9 fmol, 1.4 pg injected), 0.004 microM (0.04 pmol, 11.4 pg injected) and 0.03 microM (0.3 pmol, 91 pg injected), respectively. The method also detected the other testosterone metabolites, the 16alpha-, 16beta-, 2beta- and 2alpha-hydroxytestosterones and was then used to study the metabolism of testosterone during its absorption by rat intestine in vitro, using everted gut sacs.

[Importance of a cefpirome-vancomycin combination on bactericidal kinetics in severe MRSA infections in intensive care]. / Intérêt de l'association cefpirome-vancomycine sur la cinétique de bactéricidie dans les infections sévères à SAMR en réanimation.

UNLABELLED: Vancomycin is always the drug of choice for treatment of infections caused by methicillin-resistant Staphylococcus aureus (MRSA) in spite of his bactericidal kinetic. BACKGROUND: The aim of this study was to evaluate in vivo the improvement of bactericidal kinetic of vancomycin associated with cefpirome against MRSA infection in critically ill patients. METHODS: The prospective cross-over study was carried out in 20 patients with severe pneumonia or bacteremia. There were randomized to receive vancomycin 2 g per day (Group 1, n = 10) or vancomycin with cefpirome 2 g x 2 (Group 2, n = 10). Clinical recovery, bacteriologic parameters (bactericidal kinetic and bactericidal power in vivo at the peak and the valley), duration of ventilation and stay in ICU were comparatively explored in both groups. RESULTS: Clinical outcome did not significantly differ between Group 1 and 2. Bactericidal kinetics were better in the Group 2 (40% vs 60% after 6 hours to the dilution for 1/8e) but the difference was not significant. However, bactericidal power in sera was also better in the Group 2 with more bactericidal dilution at 1/16e (68% vs 88.8%: NS) and overall at 1/32e (10.5% vs 50%: p < 0.05) and CRP, an inflammatory marker, was significantly lower in the Group 2 than in the Group 1 (119.5 +/- 24 mg/l vs 198.6 +/- 78 mg/l: p < 0.05) on the third day.

Development and evaluation of an HPLC urinalysis screening test for occupational exposure to 3,4- and 3,5-dichloroanilines.

OBJECTIVE: In order to develop a screening test to detect human occupational exposure to aromatic amines such as 3,4-dichloroaniline (3,4-DCA) and 3,5-dichloroaniline (3,5-DCA), we first investigated the urinary excretion of these highly toxic compounds in the rat. The study was performed after both oral and dermal application, even though contact with the skin is the major route of contamination in the workplace. The aim of this study was to develop a rapid screening test for risk assessment in the workplace. METHODS: An initial group of 3 rats was treated with 40 microl of 3,4-DCA solution (30% in methanol), applied topically to the shaved dorsal skin. A second group of 3 rats were administered the same dose of the amine orally by gavage before urine sampling. The same procedure was performed with 3,5-DCA (2 other groups of 3 rats). The urine samples were collected for a period of 24 hours after treatment and the excretion of 3,4-DCA, 3,5-DCA was studied using a GC-MS and an HPLC method after urine extraction. The urine of 2 workers potentially exposed to the amines for a period of 161 and 147 days, respectively, was analyzed by the same methods with urine collection before and at the end of the work shift. RESULTS: The study of excretion in the rat showed that unchanged dichloroanilines and some metabolites were excreted 24 hours after administration of the amines. Based on these results, we propose an HPLC method for the screening of risk assessment in the workplace. The presence of 3,4-DCA and 3,5-DCA in the urine of workers showed that they were absorbing amines during the workshift. CONCLUSIONS: These results successfully allowed us to detect contamination due to 3,4-DCA and 3,5-DCA in exposed workers. The HPLC method described provides a satisfactory and sensitive procedure for urine screening in the assessment and monitoring of the occupational exposure to dichloroanilines.

[Gastrointestinal absorption of drugs through the digestive barrier]. / Le franchissement des barrières digestives.

Drug absorption through the digestive membranes occurs essentially by the paracellular route between the cells and through the tight junctions, and by the transcellular route via active or passive transfers across the membrane. Also, active transporters are able to pump substrates from the enterocytes back to the lumen via efflux proteins. These are able to slow and/or to reduce drug absorption, in particular, represent a source of variability by interactions with inducers or inhibitors such as pharmaceutical excipients. Other important factors are solubilization, drug metabolism, both in the lumen and in the enterocytes, gastric emptying and the interactions with food or between drugs.

Pharmacodynamic study of low molecular weight dermatan sulphate (Desmin) after a single subcutaneous administration in patients with renal insufficiency.

The pharmacodynamic pattern of low molecular weight dermatan sulphate (CAS 24967-94-0, Desmin-LMWDS) was studied in patients presenting chronic renal insufficiency. Three groups of six patients were defined according to their creatinine clearance: group 1, more than 50 ml/min, group 2 between 10 and 50 ml/min and group 3 lower than 10 ml/min (haemodialized patients). Desmin-LMWDS concentrations were determined with the Heptest assay and the chromogenic specific heparin cofactor II dependent anti IIa assay. In patients of group 1 affected by moderate renal insufficiency, the pharmacodynamic profiles were roughly comparable to those obtained in normal subjects. In the two other groups, the profiles were markedly modified by the renal insufficiency. The maximal concentrations were doubled and the areas under the time-activity curve were 4-fold higher in haemodialyzed (group 3) and severe renal insufficient patients (group 2) than in patients of group 1. The clearance of the anti IIa activity were 13.98 +/- 6.25 l/h; 4.12 +/- 2.64 l/h and 2.94 +/- 1.53 l/h and the half-lives were 2.79 +/- 2.60 h, 6.15 +/- 4.02 h and 11.51 +/- 6.54 h in groups 1 to 3, respectively (p < 0.05). The Desmin-LMWDS clearance was directly correlated to the creatinine clearance (r = 0.8244, n = 18, p < 0.001). Thus, as for low molecular weight heparin, renal function plays a major role in the elimination of low molecular weight dermatan sulphate.

Pharmacokinetics and bioequivalence of two trimebutine formulations in healthy volunteers using desmethyl-trimebutine levels.

Trimebutine tablets (dimethylamino-2-phenyl-2-n-butyl-3,4,5- trimethoxybenzoate maleate, CAS 34140-59-5, reference) and a new tablet formulation (Eurogalena, test) were administered in 24 healthy volunteers of both sexes according to a cross-over design, in a single dose of one 100 mg tablet of each formulation. Blood samples were drawn off over a 24-h period, before (time 0) and after each administration at specific intervals. Trimebutine and its main active metabolite, desmethyl-trimebutine, were measured in plasma using a validated HPLC method with UV detection. For both compounds, the sensitivity was 20 ng.ml-1 and the analytical method was proved to be linear for concentrations between 20 ng.ml-1 and 5000 ng.ml-1, with a variability less than 11%. The non-compartmental method was used for pharmacokinetic analysis. The confidence interval approach was used for comparison of the formulations according to the EU guidance note on bioavailability and bioequivalence on Cmax, AUC0-t and AUC0-infinity, log transformed. Tmax values were statistically compared using the Friedman non-parametric test. No trimebutine concentration was measured in the plasma samples. The obtained data with desmethyl-trimebutine proved the bioequivalence of the two tested formulations.

A pharmacokinetic interpretation of increasing concentrations of DEHP in haemodialysed patients.

The degree of exposure to DEHP was assessed in 11 patients with chronic renal failure undergoing maintenance haemodialysis. The amount of DEHP leached from the dialyser during a 4-h dialysis session was estimated by monitoring the DEHP blood concentration using a HPLC method. When a patient undergoes a dialysis treatment, the concentration of di-2-ethylhexyl phthalate (DEHP) in venous blood is increased when the blood crosses through the dialysis apparatus. This increase may be explained either because DEHP is not extracted by the dialyser or because DEHP comes from the dialysis bath due to contact of blood against plasticized pipes. To explain the increasing concentration of DEHP during treatment of renal failure using plasticized tubing, we propose a pharmacokinetic compartmental model in order to fit raw data obtained from dialysed patients and to get the amount of DEHP which enters the body by AUC calculations. Results obtained after HPLC analysis show a high degree of interpatient variability in DEHP retained. This amount can reach a toxicity level because of repetitive dialysis treatments over prolonged periods of time. In the coming years, it seems necessary to reconsider the use of DEHP as a plasticizer in medical devices. Highly unacceptable amounts of DEHP leached during the dialysis session could be easily avoided by careful selection of haemodialysis tubing.

Determination of trimebutine and desmethyl-trimebutine in human plasma by HPLC.

A simple and sensitive HPLC method has been developed to measure trimebutine (CAS 39133-31-8, maleate: CAS 34140-59-5) and its main metabolite desmethyl-trimebutine in human plasma. The method was validated according to the Washington Consensus Conference on the Validation of Analytical Methods. It involved extraction of the plasma with n-hexane containing 2-pentanol, followed by reversed-phase HPLC using a Partisil ODS2 10 microns column and UV detection at 265 nm. The retention times of the internal standard (procaine), desmethyl-trimebutine and trimebutine were 2.4, 4.3 and 6.5 min, respectively. The standard curves were linear from 20 ng.ml-1 (limit of quantitation) to 5000 ng.ml-1 for both compounds. The coefficient of variation for all the criteria of validation were less than 15%. The extraction recoveries obtained for trimebutine and desmethyl-trimebutine were about 90%. Both compounds were very stable upon storage in plasma. The method was tested by measuring the plasma concentrations following oral administration to humans during a bioequivalence study and was shown suitable for pharmacokinetic studies.

Synthesis of methylamino-2-phenyl-2-butyl-3,4,5-trimethoxybenzoate, the main bioactive metabolite of trimebutine maleate.

The first synthesis of the methylamino-2-phenyl-2-butyl-3,4,5-trimethoxybenzoate (desmethyltrimebutine) I is described. This compound is the main bioactive metabolite of trimebutine II (Debridat, CAS 39133-31-8), an antispasmodic widely used for intestinal diseases since 1969. It was used for pharmacokinetic and bioequivalence studies.

Effect of polyoxyl 35 castor oil and Polysorbate 80 on the intestinal absorption of digoxin in vitro.

Surfactants are classically used to improve the solubilization of lipophilic drugs such as digoxin. Polysorbate 80 and Cremophor EL (polyoxyl 35 castor oil) are such surfactants but they may also modulate the action of P-glycoprotein, an energy-dependent "counter-transport" system implicated in the phenomenon of multidrug resistance in cancer cells. P-glycoprotein is also present in the intestine on the apical membrane of mature enterocytes and can potentially reduce the absorption of a wide range of drugs. In this study, using the improved everted gut sac method, the effects of Polysorbate 80, Cremophor EL and cyclosporin on the absorption of digoxin were studied. An increase in the uptake of digoxin in the presence of these three products could be shown with our in vitro model. Cremophor EL and Polysorbate 80 had no toxic effects at the concentrations used. These results suggest that surfactants such as Cremophor EL and Polysorbate 80 should not only support solubilization but can also modulate the P-glycoprotein system to improve the bioavailability of poorly absorbed drugs.

Pharmacokinetics of single-dose reboxetine in volunteers with renal insufficiency.

Reboxetine is a new selective norepinephrine reuptake inhibitor (selective NRI) for the short- and long-term treatment of depression that is effective and well tolerated at a dose of 8 to 10 mg/day. This study assessed the pharmacokinetics of reboxetine in volunteers with renal impairment. A single 4 mg dose of reboxetine was administered to a total of 18 volunteers with mild (n = 6), moderate (n = 6), or severe (n = 6) renal impairment (creatinine clearance: 56-64, 26-51, and 9-19 ml/min, respectively), and reboxetine concentrations were measured in plasma by HPLC. Mean AUC infinity increased by 43% (mild vs. severe; p < 0.01) as renal function declined, while renal clearance and total urinary excretion of unchanged reboxetine decreased by 67% and 62%, respectively (mild vs. severe; p < 0.01 for both parameters). tmax and t1/2 were not significantly different between groups. In comparison with historical data from young healthy volunteers, AUC infinity and t1/2 are at least doubled in volunteers with renal impairment, while CLr is halved. This pharmacokinetic study has shown that increasing renal dysfunction leads to increasing systemic exposure to reboxetine, particularly in severe renal insufficiency, although reboxetine was well tolerated by all volunteers. Thus, a reduction of the starting dose of reboxetine to 2 mg twice daily would be prudent in patients with renal dysfunction.