Pharmacokinetic profile of long-acting injectable risperidone at steady-state: comparison with oral administration.

The single dose pharmacokinetic profiles of long-acting injectable (LAI) risperidone and oral risperidone were extrapolated to steady-state. Plasma concentrations of the active moiety (unchanged risperidone + 9-hydroxy-risperidone) were measured by radioimmunoassay up to 72 h after a single oral 1 mg dose of risperidone in healthy volunteers (n = 12), and up to 84 days after a single intramuscular injection of 50 mg LAI risperidone in schizophrenic patients (n = 26). These data were projected to multiple dose regimens (4 mg/day for the oral formulation and 50 mg every 2 weeks for LAI formulation) using the software package WinNonlin, and average steady-state pharmacokinetic profiles were predicted. The most interesting results, obtained at steady-state, were a lower predicted peak plasma level (46 vs. 62 ng/ml) and a lower predicted degree of fluctuation between Cssmax and Cssmin (53 vs 145%) with LAI compared to oral administration, which is in line with actual steady state data on LAI risperidone. In conclusion, the pharmacokinetic profile of LAI risperidone administered every 2 weeks ensures a steady-state profile with concentrations falling in the interval observed with an equivalent oral dose but with lower and less fluctuations (i.e. 1/2 weeks vs 1/day).

Inflammation increases sufentanil requirements during surgery for inflammatory bowel diseases.

BACKGROUND AND OBJECTIVE: Inflammation promotes hyperalgesia and increases opioid binding protein (alpha1-acid glycoprotein) inducing increased opioid requirement. To investigate the influence of an acute episode of inflammatory bowel disease in opioid requirement during major abdominal surgery, 17 patients with Crohn's disease, 12 patients with ulcerative colitis and seven patients without any inflammatory process (control group) were prospectively studied. Sufentanil requirements were assessed during surgery. METHODS: Sufentanil administration was adjusted when haemodynamic variables changed more than 20% of preoperative values. In a subgroup of 20 patients (Crohn's disease: 7, ulcerative colitis: 7, control group: 6), plasma concentrations of alpha1-acid glycoprotein and unbound sufentanil were measured. Total plasma clearance of sufentanil was also determined. Data presented as median (25-75 per thousand) were analysed by non-parametric and ANOVA tests. RESULTS: Despite similar surgery duration, intraoperative sufentanil requirements were significantly larger in both the Crohn's disease group (0.9 (0.6-1.6) microg kg(-1) h(-1)) and the ulcerative colitis group (1.1 (0.6-1.7) microg kg(-1) h(-1)) than in the control group (0.5 (0.4-0.5) microg kg(-1) h(-1)). Total plasma clearance of sufentanil was larger in patients with inflammatory bowel disease than in the control group. The plasma alpha1-acid glycoprotein concentration was increased in the inflammatory bowel disease group. However, the free fraction of sufentanil was similar in all three groups. The largest sufentanil consumption in patients with inflammatory bowel disease was observed during time of pain stimulation in the area of referred hyperalgesia from the affected viscus. In the control group, the sufentanil requirement was constant throughout surgery. CONCLUSION: Inflammatory bowel disease increases opioid requirement during major abdominal surgery.

Influence of peroperative opioid on postoperative pain after major abdominal surgery: sufentanil TCI versus remifentanil TCI. A randomized, controlled study.

BACKGROUND: Sufentanil and remifentanil are characterized by two different pharmacokinetic profiles. The aim of this study was to compare the effects of sufentanil and remifentanil administered using target-controlled infusion (TCI) on recovery and postoperative analgesia after major abdominal surgery. METHODS: Thirty adult patients scheduled for open colorectal surgery were included in a prospective, randomized study. Sufentanil TCI (sufentanil group) or remifentanil TCI (remifentanil group) was administered during surgery. In the remifentanil group, 30 min before the anticipated end of surgery, morphine 0.15 mg x kg(-1) was administered i.v. In the sufentanil group, an effect-site concentration of 0.25 ng x ml(-1) was targeted at extubation. In both groups, postoperative pain was controlled by titration of i.v. morphine and then patient-controlled analgesia with morphine. RESULTS: The extubation time was similar in the two groups (mean (SD) 13 (6) and 14 (6) min in the sufentanil and remifentanil groups respectively). Visual analogue scale scores were significantly greater during the first 2 h after tracheal extubation in the remifentanil group than in the sufentanil group. The time to first analgesic request in the postanaesthesia care unit was significantly longer in the sufentanil group than in the remifentanil group (55 (64) (range 2-240) vs 11 (7) (1-29) min; P<0.001). The cumulative morphine dose for titration was significantly greater in the remifentanil group (P<0.01). The cumulative morphine dose used during titration and patient-controlled analgesia was significantly greater in the remifentanil group 4, 12 and 24 h after extubation (P<0.05). CONCLUSION: TCI sufentanil (0.25 ng ml(-1) effect-site concentration at extubation) is more effective than the intraoperative combination of remifentanil TCI infusion with morphine bolus (0.15 mg x kg(-1)) for postoperative pain relief after major abdominal surgery and does not compromise extubation and recovery.

Population pharmacokinetics of cisapride in neonates.

OBJECTIVES: We conducted a population pharmacokinetic analysis of cisapride in neonates to study whether metabolic immaturity in this population may lead to increased concentrations. METHODS: Cisapride was administered orally in 91 neonates at the dose of 0.2 mg/kg four times a day. Plasma concentrations were measured using a validated HPLC method. A one-compartment model with first-order absorption was fitted to the data using NONMEM software. RESULTS: One to seven plasma samples were obtained from neonates aged 7-123 days. Cisapride concentrations ranged from 5.5 ng/mL to 172 ng/mL and were not higher than those reported in adults. The absorption constant rate was fixed to 2.5 h-1. Clearance (CL/F) and volume of distribution (V/F) both significantly correlated to weight (WT), but addition of this covariate in V/F did not improve the objective function after it was added in the CL/F covariate model. Prematurity, postnatal age, or coadministered drugs did not affect cisapride clearance. Final population pharmacokinetic parameters (interindividual variability) were: V/F=17,200 mL (90.4%) and CL/F=3.91 x WT(3/4) mL/h (36.3%). CONCLUSIONS: Our finding that cisapride clearance is primarily influenced by weight is in agreement with current recommendations of weight-adjusted doses. This study indicates that no clinically relevant maturational changes in cisapride clearance have to be considered during the first quadrimester of life.

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.

More epidural than intravenous sufentanil is required to provide comparable postoperative pain relief.

UNLABELLED: The extent to which epidurally administered sufentanil acts directly on spinal opioid receptors remains controversial. We tested the hypothesis that small-dose boluses of sufentanil, given epidurally or IV, provide comparable analgesia at similar plasma sufentanil concentrations. The lipophilicity of sufentanil makes it likely to be absorbed into fat surrounding the epidural space. We therefore also tested the hypothesis that more epidural than IV sufentanil is required to produce comparable analgesia. Analgesia and plasma sufentanil concentrations were evaluated in 20 postoperative patients randomly assigned to patient-controlled epidural or IV sufentanil. Pain was evaluated with visual analog scales by blinded observers. Sufentanil doses and plasma concentrations were measured. Analgesia was similar with epidural and IV sufentanil administration. Plasma sufentanil concentrations were virtually identical in the two groups. However, significantly larger sufentanil doses were required with epidural administration: 238 +/- 50 microg vs 160 +/- 32 microg (P < 0.01). The primary mechanism by which small-dose boluses of epidurally-administered sufentanil produce analgesia seems to be systemic absorption of the drug with subsequent recirculation to the supraspinal opioid receptors. This study demonstrates that the cumulative dose of sufentanil, when administered as a small epidural bolus, is approximately 50% more than that administered IV to provide comparable analgesia. This indicates that the bioavailability of epidurally-administered sufentanil is reduced and suggests that a large proportion of the drug may be absorbed into the epidural fat. IMPLICATIONS: More epidural than IV sufentanil was required to provide comparable postoperative pain relief and similar plasma sufentanil concentrations. These data suggest that when sufentanil is administered in small-dose boluses, much of the drug is absorbed into the epidural fat and that the primary mechanism by which epidurally administered sufentanil produces analgesia is via systemic absorption.

Effect of itraconazole on the pharmacokinetics of prednisolone and methylprednisolone and cortisol secretion in healthy subjects.

AIMS: Itraconazole is a potent inhibitor of CYP3A4 activity and is often used in combination with corticosteroids. Since the latter are partly metabolized by CYP3A4, we studied the interaction between itraconazole, prednisone and methylprednisolone in healthy male subjects. METHODS: The effects of 4 days administration of oral itraconazole (400 mg on the first day then 200 mg day-1 for 3 days) on the pharmacokinetics of prednisolone after a single oral dose of prednisone (60 mg) and the pharmacokinetics of methylprednisolone after single oral dose of methylprednisolone (48 mg) were studied in 14 healthy male subjects in a two-period cross-over trial. Plasma cortisol concentrations were determined as a pharmacodynamic index. RESULTS: Itraconazole increased the mean area under the methylprednisolone concentration-time curve from 2773 ng ml-1 h to 7011 ng ml-1 h (P < 0.001) and the elimination half-life from 3.2 h to 5.5 h (P < 0.001). The pharmacokinetics of prednisolone were unchanged. Cortisol concentrations at 24 h were lower after administration of methylprednisolone with itraconazole than after methylprednisolone alone (24 ng ml-1 vs 109 ng ml-1, P < 0.001). CONCLUSIONS: Itraconazole increased methylprednisolone concentrations markedly with enhanced suppression of endogenous cortisol secretion, but had no effect on prednisolone pharmacokinetics. The pharmacokinetic interaction between methylprednisolone and itraconazole is probably related to inhibition of hepatic CYP3A4 activity by itraconazole.

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.

A randomized, double-blinded comparison of intrathecal morphine, sufentanil and their combination versus IV morphine patient-controlled analgesia for postthoracotomy pain.

UNLABELLED: We compared the analgesic effect of lumbar intrathecal (IT) 0.5 mg morphine (Group M, n = 10), 50 microg sufentanil (Group S, n = 10), and their combination (Group S-M, n = 10) given before general anesthesia and patient-controlled analgesia with IV morphine (Group C, n = 19) in a randomized, double-blinded study performed in patients undergoing thoracotomy. Pain visual analog scale (VAS) and morphine consumption were assessed for 24 h. In Group S-M the number of patients initially titrated with IV morphine was less than in group C (30 vs 84%, P < 0.05). Morphine requirement was higher in Group C (71 +/- 30 mg) than in Groups S (46 +/- 34 mg, P < 0.05), M (38 +/- 31 mg, P < 0.05) and S-M (23 +/- 16 mg, P < 0.01). VAS scores were significantly decreased during the first 0-11 postoperative h at rest and during the first 0-8 postoperative h on coughing in Groups M and S-M rather than in Group C. The incidence of side effects was infrequent except for urinary retention. Preoperative IT morphine or combined sufentanil and morphine could be given as a booster to achieve rapidly effective analgesia in the immediate postoperative period. IMPLICATIONS: As compared with IV patient-controlled analgesia, intrathecal morphine or combined sufentanil and morphine provided superior postoperative pain relief both at rest (11 h) and on coughing (8 h) than did IV patient-controlled analgesia morphine alone. IV morphine requirement was decreased during the first postoperative day after posterolateral thoracotomy.

Pharmacokinetics of transdermal fentanyl in the peri-operative period in young children.

The pharmacokinetics of transdermal fentanyl were assessed in eight children aged 18-60 months, weighing 11-20 kg and monitored postoperatively in the intensive care unit. A patch, delivering 25 microg.h-1 of fentanyl, was applied for 72 h from the induction of anaesthesia. Plasma fentanyl concentrations were measured over 144 h. Mean (SD) peak concentration of fentanyl was 1.7 (0.66) ng.ml-1 and time to reach maximal plasma concentration was 18 (11) h. The elimination half-life was 14.5 (6.2) h, and the area under the curve for plasma fentanyl concentration (0-144 h) was 86.8 (27) ng.h.ml-1. Maximal fentanyl concentration was negatively correlated with patient age (r = - 0.71; p = 0.049) but not with body weight. These results suggest that the pharmacokinetics of transdermal fentanyl in children are similar to those in adults.

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.

Itraconazole lung concentrations in haematological patients.

Itraconazole distribution is largely dependent on its high liposolubility. Intrapulmonary lung concentrations remain unknown in haematological patients. We report itraconazole lung concentrations in such patients treated with itraconazole. Itraconazole and hydroxyitraconazole were measured by high-performance liquid chromatography in concomitant blood samples and lung post-mortem biopsies (three cases) or lung lobectomy (one case). These itraconazole and metabolite lung concentrations were sufficient to be active on Aspergillus.

Cardiac baroreflex during the postoperative period in patients with hypertension: effect of clonidine.

BACKGROUND: Patients with essential hypertension show altered baroreflex control of heart rate, and during the perioperative period they demonstrate increased circulatory instability. Clonidine has been shown to reduce perioperative circulatory instability. This study documents changes in measures of heart rate control after surgery in patients with essential hypertension and determines the effects of clonidine on postoperative heart rate control in these patients. METHODS: Using a randomized double-blind placebo-controlled design, 20 patients with essential hypertension (systolic pressure >160 mm Hg or diastolic pressure >95 mm Hg for > or =1 yr) were assigned to receive clonidine (or placebo), 6 microg/kg orally 120 min before anesthesia and 3 microg/kg intravenously over 60 min before the end of surgery. The spontaneous baroreflex ("sequence") technique and analysis of heart rate variability were used to quantify control of heart rate at baseline, before induction of anesthesia, and 1 and 3 h postoperatively. RESULTS: Baroreflex slope and heart rate variability were reduced postoperatively in patients given placebo but not those given clonidine. Clonidine resulted in greater postoperative baroreflex slope and power at all frequency ranges compared with placebo (4.9+/-2.9 vs. 2.2+/-2.1 ms/mm Hg for baroreflex slope, 354+/-685 vs. 30+/-37 ms2/Hz for high frequency variability). Clonidine also resulted in lower concentrations of catecholamine, decreased mean heart rate and blood pressure, and decreased perioperative tachycardia and hypertension. CONCLUSIONS: Patients with hypertension exhibit reduced heart rate control during the recovery period after elective surgery. Clonidine prevents this reduction in heart rate control. This may represent a basis for the improved circulatory stability seen with perioperative administration of clonidine.

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 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.

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.

Pharmacokinetics of beta-adrenoceptor blockers in obese and normal volunteers.

AIMS: Obesity can modify the pharmacokinetics of lipophilic drugs. As beta-adrenoceptor blockers (BB) are often prescribed for obese patients suffering from hypertension or coronary heart disease, this study compares the pharmacokinetics of lipophilic beta-adrenoceptor blockers in obese and control subjects. METHODS: Nine obese (157 +/- 24% of ideal body weight (IBW) mean +/- s.d.) and nine non-obese healthy volunteers (98 +/- 10% IBW), aged 32 +/- 9 years, were included in the study. Subjects were randomly given a single i.v. infusion of one of the following racemic beta-adrenoceptor blockers, whose doses (expressed as base per kg of IBW) were: propranolol (0.108 mg), labetalol (0.99 mg) and nebivolol (0.073 mg). The plasma concentrations of unchanged drugs were measured by h.p.l.c. The ionisation constants and lipophilicity parameters of beta-adrenoceptor blockers were assessed. RESULTS: The pharmacokinetic data for the three drugs were qualitatively similar. There was a trend towards a greater total distribution volume (Vss) in obese patients than in controls. However, Vss expressed per kg body weight was slightly smaller in obese patients. The relationship between Vss and lipophilicity of five beta-adrenoceptor was studied by combining the current results with those previously obtained with a moderately lipophilic drug (bisoprolol) and a hydrophilic one (sotalol). The Vss of the five drugs was positively and well-correlated (r2 = 0.90; P < 0.01) with their distribution coefficient at pH 7.4 (log D7.4), but not with their partition coefficients. The linear regression coefficients for lean and obese subjects were very similar. CONCLUSIONS: Lipophilic beta-adrenoceptor blockers seem to diffuse less into adipose than into lean tissues. All electrical forms of the drugs (i.e. cations, neutral forms, or zwitterions) present at physiological pH contribute to their tissue distribution, in both obese and lean subjects. Their tissue distribution in obese patients could be restricted by the sum of hydrophobic forces and hydrogen bonds they elicit with macromolecules in lean tissues.

Lack of effect of amitriptyline on risperidone pharmacokinetics in schizophrenic patients.

The interaction between plasma concentrations of the tricyclic antidepressant amitriptyline and the metabolism of the new antipsychotic risperidone was studied in 12 patients with chronic schizophrenia. Each patient received 3 mg risperidone twice a day for 28 days. Amitriptyline was coadministered at doses of 50 mg/day on day 15 and 100 mg/day on days 16 to 21. Amitriptyline did not significantly affect the mean plasma concentrations or pharmacokinetics of risperidone in schizophrenic patients or influence the antipsychotic fraction (the total concentration of risperidone and 9-hydroxyrisperidone, its primary and biologically active metabolite). These results suggest that risperidone dose need not be adjusted when coadministered with amitriptyline at doses up to 100 mg/day in schizophrenic patients.

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.