Pharmacokinetics of itraconazole oral solution in allogeneic bone marrow transplant patients receiving total body irradiation.

A prospective study of the pharmacokinetics of itraconazole solution was performed in 11 patients who underwent allogeneic BMT (day of BMT = day 0) after a conditioning regimen including total body irradiation (TBI). Itraconazole solution (400 mg once a day) was given 7 days before BMT and continued up to the end of neutropenia unless another antifungal treatment was necessary. Blood samples were collected before itraconazole intake (Cmin) and 4 h later (Cmax) every other day for assays of itraconazole (ITRA) and its active metabolite hydroxy-itraconazole (OH-ITRA). The mean values of Cmin ITRA and OH-ITRA, respectively, were 287 +/- 109 ng/ml and 629 +/- 227 ng/ml at day -1 and 378 +/- 147 ng/ml and 725 +/- 242 ng/ml at day +1. The maximum Cmin values were observed at day +3. Six patients at day -1 (54%) and 8 at day +1 (72%) had satisfactory residual plasma concentrations of at least 250 ng/ml of unchanged ITRA. From day +1 to day +9, eight patients discontinued the itraconazole treatment, five of them had satisfactory plasma residual concentrations at this time. This work shows a good bioavailability of itraconazole oral solution during the early phase after allogeneic BMT, but more data are needed for the late phases.

Pilot study on the effect of tourniquet use on sufentanil pharmacokinetics.

STUDY OBJECTIVE: To test our hypothesis that sequestration of sufentanil can occur during surgery when a pneumatic tourniquet is used. DESIGN: Prospective, randomized study. SETTING: Operating room and recovery room of a university hospital. PATIENTS: 16 ASA physical status I and II patients scheduled for orthopedic surgery with pneumatic tourniquet use. INTERVENTION: Patients were randomized to three groups. Sufentanil was given intravenously at 0.5 microg kg(-1) bolus at the same time that a constant infusion was started at 0.5 microg kg h(-1). In Group 1, continuous infusion of sufentanil was stopped when the tourniquet was released (n = 6). In Group 2, continuous infusion of sufentanil was stopped 15 minutes after tourniquet release (n = 6). In Group 3, as a control group, the sufentanil bolus was started after tourniquet inflation (n = 4). MEASUREMENTS: Plasma sufentanil concentrations were determined by radioimmunoassay. To compare pharmacokinetic results, a simulation of the sufentanil plasma concentrations was achieved. MAIN RESULTS: Exsanguination and inflation of the pneumatic tourniquet had no significant effect on pharmacokinetic results. In 75% of patients, a significant increase in sufentanil plasma concentration occurred between 30 and 60 minutes after tourniquet deflation in all three groups, probably as a result of patient mobilization. One respiratory distress event occurred in a Group 2 patient following extubation at 55 minutes after the end of the sufentanil infusion. The rebound of sufentanil concentration was higher in Group 2; it may be due to a reduced effect of the restoring circulation in the ischemic leg by a prolonged infusion after tourniquet deflation. CONCLUSIONS: Using a pneumatic tourniquet induces transient changes in the pharmacokinetics of sufentanil. These changes may have clinical relevance during the first hour after tourniquet release.

[Peroperative perfusion of fentanyl or sufentanil: plasma concentrations and postoperative respiratory changes]. / Perfusion peropératoire de fentanyl ou de sufentanil: concentrations plasmatiques et modifications respiratoires postopératoires.

This study was designed to assess postoperatively the time course of respiratory depression due to fentanyl (F) or sufentanil (S), as well as the plasma concentrations. Seventy patients scheduled for orthopaedic surgery lasting more than 3 hours were randomly assigned to two groups, F (n = 8) or S (n = 9). Anaesthesia was induced with etomidate (0.3 mg.kg-1), droperidol (0.15 mg.kg-1), vercuronium (0.1 mg.kg-1), a loading dose of either F (10 micrograms.kg-1) or S (1 microgram.kg-1), and maintained with 60% nitrous oxide in oxygen, and an infusion of F (6 micrograms.kg-1.h-1) or S (0.6 microgram.kg-1.h-1). Mechanical ventilation was maintained postoperatively in the recovery room until the patient could be extubated. PetCO2, SpO2, fR and F and S plasma concentrations were assessed at the end of the opioid infusion, at extubation, every hour for the first 6 hours, and thereafter every 2 h for a further 10 and 18 h. Time to extubation was the same in both groups (301 +/- 141 and 307 +/- 148 min). At the time, plasma concentrations of F and S were 1.35 +/- 0.9 ng.ml-1 and 0.14 +/- 0.07 ng.ml-1 respectively. Secondary peaks in plasma concentration (78% mean increase in comparison to the previous figure) were observed in 6 patients in group F. No similar peaks occurred in group S. Mean elimination half-life was shorter with sufentanil (457 +/- 130 min) than with fentanyl (325 +/- 132 min) (not significant). The results of this study suggest that sufentanil results less frequently in postoperative secondary peaks than fentanyl.

[Comparison of the pharmacokinetics of etomidate in children and in adults]. / Comparaison de la pharmacocinétique de l'étomidate chez l'enfant et chez l'adulte.

Etomidate pharmacokinetics were compared in 12 children (P group) (age 7 to 13 years, weight 22 to 48 kg) and in 4 adult women (A group) (age 28 to 52 years, weight 46 to 72 kg), A.S.A. 1, undergoing minor non abdominal surgery. They were unpremedicated and anaesthetized with alfentanil 100 micrograms.kg-1, and isoflurane 2 vol % in N2O/O2 (1/1). Etomidate was administered as a bolus: 0.3 mg.kg-1 in adults and 0.4 mg.kg-1 in children. Venous plasma samples were frozen until further etomidate assay with a HPLC technique. In all patients but two children, data were fitted to a three rather than a two compartment model. Differences between groups (mean +/- SD values) included Vdc (P: 0.66 +/- 0.31 l.kg-1; A: 0.27 +/- 0.15 l.kg-1; p less than 0.01), t1/2 pi (P: 5.4 +/- 2.9 min; A: 2.7 +/- 5.7 min; p less than 0.05) and plasma clearance (P: 17.2 +/- 4.6 ml.kg-1.min-1; A: 10.9 +/- 3.3 ml.kg-1.min-1; p less than 0.05). No statistical difference was found between A and P groups for the following parameters: t1/2 alpha (37.1 +/- 12.0 min vs 26.8 + 15.1 min), t1/2 beta (260 +/- 99 min vs 175 +/- 99 min), Vdss (2.5 +/- 1.11.kg-1 vs 2.8 +/- 1.61.kg-1), Vd beta (4.1 +/- 2.41.kg-1 vs 4.0 +/- 2.21.kg-1), and MRT (228 +/- 80 min vs 172 +/- 101 min). No age-related difference was found inside P group with regard to pharmacokinetic parameters. In conclusion, a 30% higher etomidate bolus dosage is required in children than in adults to achieve similar plasma concentrations, due to a higher volume of the initial compartment. In comparison to adults the higher clearance suggests higher maintenance dose requirements in children.

Determination of risperidone and 9-hydroxyrisperidone in human plasma by high-performance liquid chromatography with electrochemical detection.

A method for the determination of risperidone and its active metabolite 9-hydroxyrisperidone in human plasma has been developed. The procedure involved a multi-step liquid-liquid extraction with an internal standard. The parent drug and its metabolite were separated on a cyano column used in the reversed-phase model. The coulometric detection allows quantification in the range 2-100 ng/ml. The precision, accuracy and specificity have been checked, and show that the method is reliable for clinical studies.

Gas--liquid chromatographic determination of toloxatone in human plasma. Routine analysis of a wide range of drug concentrations using a nitrogen-selective detector.

A selective and sensitive gas--liquid chromatographic (GLC) method has been developed for the measurement of toloxatone at therapeutic concentrations in plasma. The technique is based on a single extraction from plasma at pH 10, the preparation of a trimethylsilyl derivative and detection by a nitrogen-selective detector. The traditional calibration curve, peak-area ratio of toloxatone to internal standard versus toloxatone plasma concentration, was slightly concave for the wide concentration considered (10-3000 ng/ml). As a consequence, the linear least-squares regression analysis gave a negative intercept on the gamma-axis which affected quantitation accuracy of low plasma concentration values. A calibration method taking into consideration the non-linearity of the calibration curve is proposed. The characteristics of the detector were examined in order to analyse response linearity and sensitivity. A linear relationship was found between background current and detector sensitivity.

Reversed-phase high-performance liquid chromatographic separation of 14C-labelled toloxatone and its metabolites.

A method for the analytical and micropreparative separation of toloxatone and its urinary metabolites in man is described. Toloxatone was given as an aqueous solution and was labelled with 14C. Following solvent extraction of urine, before and after enzymatic hydrolysis, one-step thin-layer chromatography on silica gel in combination with reversed-phase high-performance liquid chromatography, gave a good micropreparative separation for mass spectrometric analysis. After lyophilization of the high-performance liquid chromatographic fractions, the purity of the metabolites was checked by thin-layer chromatography. Acetic acid was chosen to regulate the pH of the mobile phase (acetonitrile-water) because it can be easily removed by lyophilization when a preparative separation is desired. The retention times as a function of the pH have been evaluated. Formic acid is also proposed for the optimization of the high-performance liquid chromatographic analysis. The quantitative analysis of 14C-labelled toloxatone and its metabolites was carried out, after solvent extraction of 2 ml of urine, using the same high-performance liquid chromatographic method with off-line and flow-through radioactivity detection.

Determination of low plasma concentrations of 3-methoxy-4-hydroxyphenylethylene glycol using gas chromatography-negative-ion chemical ionization mass spectrometry.

Gas chromatography-negative-ion chemical ionization mass spectrometry (GC-NICI-MS) allowed the detection of extremely low plasma concentrations of 3-methoxy-4-hydroxyphenylethylene glycol (MHPG). Glucuronide and sulphate conjugates of MHPG were determined after enzymatic hydrolysis of plasma with beta-glucuronidase-arylsulphatase. A 1-ml plasma sample was extracted at the pH of the hydrolysis (pH 4.8) with ethyl acetate, and the dry extract was derivatized with pentafluoropropionic anhydride in ethyl acetate. After evaporation of the solvent, the residue was dissolved in benzene and an aliquot was analysed by GC-NICI-MS. A trideuterated analogue of MHPG was used as an internal standard. Negative-ion chemical ionization of the pentafluoropropionyl derivatives was carried out using ammonia. The ion-molecule adducts at m/e 766 and 785 (MHPG) and m/e 769 and 788 (internal standard) were formed from the pentafluoropropionyl derivatives with the ions of m/e 163 (CF3CF2COO-) and m/e 144 (loss of fluorine from m/e 163). The concentrations of the ions of m/e 163 and 144 play a major role in the sensitivity and precision of this technique, which allows the detection of free MHPG plasma concentrations as low as 100 pg/ml in routine analysis.

Hepatic disposition of alfentanil and sufentanil in patients undergoing orthotopic liver transplantation.

Alfentanil and sufentanil are used in the anesthetic management of patients undergoing orthotopic liver transplantation (OLT) and are extensively metabolized by the liver. We examined the influence of OLT on the removal of these opioids. 14 patients undergoing OLT were given either alfentanil (40 micrograms/kg intravenous [IV] bolus) or sufentanil (5 micrograms/kg IV bolus) during the induction of anesthesia, followed by infusion during surgery (1 microgram.kg-1.min-1 alfentanil or 0.01 microgram.kg-1.min-1 sufentanil) and the postoperative period (0.5 microgram.kg-1.min-1 or 0.005 microgram.kg-1.min-1). A catheter was inserted into the hepatic vein to determine the drugs' hepatic extraction coefficient and hepatic clearance. The hepatic extraction coefficient was 0.14 for alfentanil and 0.35 for sufentanil. The total and hepatic clearance of alfentanil were similar, while the hepatic clearance of sufentanil was 50% of the total clearance (P < 0.05). The total clearance of alfentanil was significantly linked to its hepatic clearance (r2 = 0.81, P < 0.001). We conclude that the total clearance of sufentanil is greater than its hepatic clearance. This difference suggests that there is extrahepatic metabolism of sufentanil in patients undergoing OLT.

Fentanyl versus sufentanil: plasma concentrations during continuous epidural postoperative infusion in children.

No pharmacokinetic data are available with respect to the plasma concentrations and fentanyl or sufentanil during epidural administration in children. This double-blind randomized study included 12 children (5-12 yr). Patients in group F were given an epidural loading dose of fentanyl 1.5 micrograms kg-1 and in group S sufentanil 0.6 microgram kg-1. Both groups then received a continuous epidural infusion of bupivacaine 5 mg kg-1 day-1 with either fentanyl 5 micrograms kg-1 day-1 or sufentanil 2 micrograms kg-1 day-1. An epidural PCA system was also given to the children (bolus: bupivacaine 0.2 mg kg-1 and fentanyl 0.2 microgram kg-1 or sufentanil 0.08 microgram kg-1). Maximal median concentrations of plasma (0.117-0.247 ng ml-1 for fentanyl and 0.027-0.074 ng ml-1 for sufentanil) were reached approximately 30 and 20 min respectively after the loading doses. These values were similar to those measured after 48 h.

Pharmacokinetics of itraconazole (oral solution) in two groups of human immunodeficiency virus-infected adults with oral candidiasis.

The pharmacokinetics of itraconazole formulated in a hydroxypropyl-beta-cyclodextrin oral solution was determined for two groups of human immunodeficiency virus (HIV)-infected adults with oral candidiasis (group A, 12 patients with CD4+ T-cell count of >200/mm3 and no AIDS, and group B, 11 patients with CD4+ T-cell count of <100/mm3 and AIDS). Patients received 100 mg of itraconazole every 12 h for 14 days. Concentrations of itraconazole and hydroxyitraconazole, the main active metabolite, were measured in plasma and saliva by high-performance liquid chromatography. Pharmacokinetic parameters determined at days 1 and 14 (the area under the concentration-time curve from 0 to 10 h, the maximum concentration of drug in plasma [Cmax], and the time to Cmax) were comparable in both groups. Trough levels in plasma (Cmin) were similar in both groups for the complete duration of the study. An effective concentration of itraconazole in plasma (>250 ng/ml) was reached at day 4. At day 14, Cmin values of itraconazole were 643 +/- 304 and 592 +/- 401 ng/ml for groups A and B, respectively, and Cmin values of hydroxyitraconazole were 1,411 +/- 594 and 1,389 +/- 804 ng/ml for groups A and B, respectively. In saliva, only unchanged itraconazole was detected, and mean concentrations were still high (>250 ng/ml) 4 h after the intake, which may contribute to the fast clinical response. In conclusion, the oral solution of itraconazole generates effective levels in plasma and saliva in HIV-infected patients; its relative bioavailability is not modified by the stage of HIV infection.

The effects of meperidine and sufentanil on the shivering threshold in postoperative patients. pascal.alfonsi@apr.ap-hop-paris.fr.

UNLABELLED: BACKGROUND. Meperidine (pethidine) reportedly treats postoperative shivering better than equianalgesic doses of other mu-receptor agonists. The authors' first goal was to develop a method to accurately determine postoperative shivering thresholds, and then to determine the extent to which meperidine and sufentanil inhibit postoperative shivering. METHODS: A computer-controlled infusion was started before operation in 30 patients, with target plasma concentrations of 0.15, 0.30, or 0.60 microg/ml meperidine or 0.1, 0.15, or 0.2 ng/ ml sufentanil targeted; patients were randomly assigned to each drug and concentration. The infusion was continued throughout surgery and recovery. Anesthesia was maintained with nitrous oxide and isoflurane. Core temperatures were approximately 34 degrees C by the end of surgery. The compensated core temperature at which visible shivering and a 20% decrease in steady-state oxygen consumption was recorded identified the shivering threshold. A blood sample for opioid concentration was obtained from each patient at this time. The ability of each opioid to reduce the shivering threshold was evaluated using linear regression. RESULTS: End-tidal isoflurane concentrations were <0.2% in each group at the time of extubation, and shivering occurred approximately 1 h later. Meperidine linearly decreased the shivering threshold: threshold (degrees C) = -2.8 x [meperidine (microg/ml)] + 36.2; r2 = 0.64, P = 0.0005. Sufentanil also linearly decreased the shivering threshold: threshold (degrees C) = -7.8 x [sufentanil (ng/ ml)] + 36.9; r2 = 0.46, P = 0.02. CONCLUSIONS: At a given dose, sufentanil inhibited shivering 2,800 times better than meperidine. However, the equianalgesic ratio of these drugs is approximately 4,900. That is, meperidine inhibited shivering better than would be expected based on the equianalgesic potency ratio. These data are thus consistent with clinical observations suggesting that meperidine indeed possesses special antishivering activity.

Pharmacokinetics of itraconazole oral solution in neutropenic children during long-term prophylaxis.

We investigated the pharmacokinetics and safety of an oral solution of itraconazole in two groups of neutropenic children stratified by age. Effective concentrations of itraconazole in plasma were reached quickly and maintained throughout treatment. The results indicate a trend toward higher concentrations of itraconazole in plasma in older children.

Pharmacokinetics of sabeluzole and dextromethorphan oxidation capacity in patients with severe hepatic dysfunction and healthy volunteers.

AIMS: The primary objective of this study was to determine how the pharmacokinetics of sabeluzole, an investigational drug with specific effects on memory and learning abilities, are affected by chronic liver disease. Since sabeluzole is metabolised by CYP2D6, a secondary objective was to study the correlation between CYP2D6 activity (as assessed by the dextromethorphan dextrorphan metabolic ratio) and hepatic dysfunction. METHODS: The single-dose pharmacokinetics of sabeluzole (10 mg) was compared in 10 healthy Caucasian subjects and 10 patients with severe hepatic dysfunction. The urinary dextromethorphan/dextrorphan (DMP/DRP) metabolic ratio was determined after intake of 20 mg dextromethorphan (NODEX capsules). RESULTS: The terminal half-life of sabeluzole was significantly prolonged in subjects with severe hepatic dysfunction vs healthy subjects (respectively 39.3 +/- 11.5 h; 17.5 +/- 10.2 h (mean +/- s.d.)). The areas under the curve (AUC) were significantly higher in subjects with severe hepatic dysfunction than in healthy volunteers (681 +/- 200 ng ml(-1) h vs 331 +/- 282 ng ml(-1) h). There was a significant correlation between the AUC(0,infinity) and the DMP/DRP metabolic ratio in healthy volunteers and subjects with severe hepatic dysfunction. AUC was greater and elimination of sabeluzole slower in poor metabolizers compared with extensive metabolizers. CONCLUSIONS: These results suggest that a) sabeluzole dose should be reduced in patients with severe hepatic dysfunction and b) the AUC of sabeluzole is linked to individual CYP2D6 activity.

Pharmacokinetic study and cardiovascular monitoring of nebivolol in normal and obese subjects.

OBJECTIVE: The pharmacokinetics of a single i.v. dose of the new racemic beta-adrenoceptor-blocker nebivolol [0.073 mg base.kg-1 ideal body weight (IBW)] was studied in 9 obese (157% IBW) and 9 non-obese healthy volunteers (98% IBW). Each group contained 4 men and 5 women, aged 32 years, including one poor hydroxylator (dextrometorphan test). METHODS: The cardiovascular effects of nebivolol are significant decreases in systolic and diastolic blood pressure, heart rate and cardiac output, which last up to 4-5 h. The plasma concentrations of the separate d- and l- enantiomers of nebivolol, with and without hydroxylated metabolite, were measured by radioimmunoassay and the unchanged racemate by high-pressure liquid chromatography (HPLC). The pharmacokinetic parameters for each form were calculated separately. RESULTS: The main pharmacokinetic parameters of unchanged nebivolol in extensive metabolizers were (controls): distribution volume at steady state (Vss) 673 l; volume corrected by real body weight (Vss.kg-1) 11.2 l.kg-1; total clearance (CL) 51.6 h-1; and terminal half-life (t1/2) 10.3 h. The Vss (898 l) and CL (71.6 l.h-1) were significantly higher in obese patients. But Vss.kg-1 (9.4 l.kg-1) and t1/2 (10.0 h) were not significantly different from those in controls. The CL was clearly reduced (15-18 l.h-1) and the t1/2 prolonged (32-34 h) in poor hydroxylators, in both control and obese subjects. The pharmacokinetic parameters of the separate unchanged enantiomers were similar to those of the racemate in both groups. The pharmacokinetics of l-nebivolol were more influenced by the hydroxylation phenotype than those of d-nebivolol. The trend of the results for the sum of each enantiomer plus its metabolite, was similar to those for the unchanged form. CONCLUSION: The distribution of nebivolol in the adipose tissue in obese subjects is limited, despite its high lipophilicity. The differences between obese and non-obese subjects were not clinically relevant.