Clinical pharmacokinetics of the CD19 receptor-directed tyrosine kinase inhibitor B43-Genistein in patients with B-lineage lymphoid malignancies

The authors examined the pharmacokinetics of the CD19 receptor-directed tyrosine kinase inhibitor B43-Genistein in 17 patients (4 children, 13 adults) with B-lineage lymphoid malignancies, including 12 patients with acute lymphoblastic leukemia (ALL) and 5 patients with non-Hodgkin's lymphoma (NHL). The immunoconjugate was administered intravenously as a 1-hour continuous infusion at a dose level of either 0.1 mg/kg (N = 12) or 0.18 mg/kg (N = 5), and the plasma concentration-time data were modeled by using the WinNonlin program to estimate the pharmacokinetic parameters. Pharmacokinetic analyses revealed a plasma half-life of 19 +/- 4 hours, mean residence time of 22 +/- 4 hours, and a systemic clearance of 18 +/- 2 mL/h/kg. The average (mean +/- SEM) values for the maximum plasma concentration Cmax, volume of distribution at steady state (Vss), and area under curve (AUC) were 1092 +/- 225 ng/ml, 291 +/- 37 mL/kg, and 9987 +/- 2021 micrograms x h/L, respectively. The AUC values were higher at the 0.18 mg/kg dose level than at the 0.1 mg/kg dose level (16,848 +/- 5118 micrograms x h/L vs. 7128 +/- 1156 micrograms x h/L, p = 0.009). Patients with ALL had a significantly larger volume of distribution at steady state (332 +/- 47 mL/kg vs. 191 +/- 12 mL/kg, p = 0.04), faster clearance (21 +/- 3 mL/h/kg vs. 11 +/- 2 mL/h/kg, p = 0.03), and lower dose-corrected AUC than patients with NHL (6010 +/- 836 micrograms x h/L vs. 12,044 +/- 2707 micrograms x h/L, p = 0.006). There was a trend toward faster clearance rates (23 +/- 4 mL/h/kg vs. 16 +/- 3 mL/h/kg, p = 0.1), shorter elimination half-lives (5.7 +/- 3.6 hours vs. 13 +/- 8.8 hours, p = 0.1), and shorter mean residence times (11 +/- 3 hours vs. 25 +/- 5 hours, p = 0.08) for non-Caucasian patients as compared to Caucasian patients. When compared to adult patients, pediatric patients showed a significantly larger volume of distribution at steady state (418 +/- 82 mL/kg vs. 252 +/- 34 mL/kg, p = 0.02) and a longer elimination half-lives (18.4 +/- 13.6 hours vs. 8.7 +/- 6.7 hours, p = 0.04). The pharmacokinetics of B43-Genistein was not affected by the gender of the patients or by bone marrow transplantation in past medical history. Overall, B43-Genistein showed favorable pharmacokinetics in this heavily pretreated leukemia/lymphoma patient population, which is reminiscent of its recently reported favorable pharmacokinetics in cynomolgus monkeys. To our knowledge, this is the first clinical pharmacokinetics study of a tyrosine kinase inhibitor containing immunoconjugate.     

Pharmacokinetics of tinidazole in chronic renal failure and in patients on haemodialysis.

The pharmacokinetics of tinidazole after infusion (800 mg in 15 min) were studied in 12 patients with chronic renal failure (RI) and in five patients undergoing regular dialysis treatment (RD). Tinidazole elimination plasma half-life was 15.09 +/- 0.68 h (mean +/- s.e. mean) (RI) and 12.9 +/- 1.0 h after dialysis (RD), but there was a significant decrease in half-life during dialysis (4.25 +/- 0.43 h) P less than 0.001). The apparent volume of distribution (0.64 +/- 0.03 l/kg) was equal to extra and intracellular water volume and tinidazole was little bound to plasma protein (8%). There was a slight sex difference in apparent volume of distribution between male patients (0.70 +/- 0.09 l/kg) and female patients (0.59 +/- 0.10 l/kg) (P = 0.07), but as body clearance decreases in the same order, there was no modification of plasma half-life. In renal failure, pharmacokinetics of tinidazole were not disturbed because no correlation between half-life, body clearance and creatinine clearance occurred; urine elimination was about 7% of administered dose. Plasma clearance during dialysis was 49.9 +/- 3.2 ml/min and about 43% of the available drug was eliminated during the 6 h dialysis procedure. These results suggest that an additional half-dose infusion should be given after the end of dialysis in patients undergoing regular dialysis treatment.     

Methylprednisolone pharmacokinetics after intravenous and oral administration.

1. The pharmacokinetics of methylprednisolone (MP) were studied in five normal subjects following intravenous doses of 20, 40 and 80 mg methylprednisolone sodium succinate (MPSS) and an oral dose of 20 mg methylprednisolone as 4 x 5 mg tablets. Plasma concentrations of MP and MPSS were measured by both high performance thin layer (h.p.t.l.c.) and high pressure liquid chromatography (h.p.l.c.). 2. The mean values (+/- s.d.) of half-life, mean residence time (MRT), systemic clearance (CL) and volume of distribution at steady state (Vss) of MP following intravenous administration were 1.93 +/- 0.35 h, 3.50 +/- 1.01 h, 0.45 +/- 0.12 lh-1 kg-1 and 1.5 +/- 0.63 1 kg-1, respectively. There was no evidence of dose-related changes in these values. The plasma MP concentration-time curves were superimposable when normalized for dose. 3. The bioavailability of methylprednisolone from the 20 mg tablet was 0.82 +/- 0.11 (s.d.). 4. In vivo hydrolysis of MPSS was rapid with a half-life of 4.14 +/- 1.62 (s.d.) min, and was independent of dose. In contrast, in vitro hydrolysis in plasma, whole blood and red blood cells was slow; the process continuing for more than 7 days. Sodium fluoride did not prevent the hydrolysis of MPSS.     

Gentamicin bioavailability and single-dose pharmacokinetics in spinal cord injury

The rate and completeness of absorption of gentamicin from muscle (healthy and paralyzed) and gentamicin disposition kinetics following a single intravenous infusion were studied in nonobese, healthy male volunteers with functionally complete, chronic (greater than one year duration) spinal cord injury (SCI) and in able-bodied controls. Pharmacokinetic parameters were derived using compartmental and model-independent analyses. The absolute bioavailability of gentamicin was complete and did not differ from control values using both model-independent (LAGRAN) and model-dependent (ADAPT) analyses. The rate of gentamicin absorption in patients with SCI was, however, significantly slower, with a mean absorption time of 2.55 h compared with 0.96 h in able-bodied controls (p less than or equal to 0.05). Mean volume of distribution steady-state (Vssd) of gentamicin was demonstrated to be 33-47 percent greater in spinal cord injury than in controls (p less than 0.05). We conclude that the absorption of gentamicin from paralyzed muscle is significantly impaired, and in conjunction with an increase in Vssd results in delayed, decreased peak serum levels in patients with SCI.     

Mefloquine disposition in normals and in patients with severe Plasmodium falciparum malaria

Mefloquine pharmacokinetics were studied in Kenyan African normal volunteers and in patients with severe acute attack of Plasmodium falciparum malaria. Peak concentrations were achieved in both groups at 20-24 hours. The mean half-life of elimination was 385 +/- 150 hours (mean +/- SD) in normal subjects while in severe malaria it was 493 +/- 215 hours which was significantly longer (P less than or equal to 0.001). The volume of distribution was significantly smaller in severe malaria where it was 30.76 +/- 10.50 l/kg (mean +/- SD) while in the normal subjects it was 40.90 +/- 20.70 l/kg (mean +/- SD) (P less than or equal to 0.001). The total body clearance in severe malaria was 3.75 +/- 1.51 l/h (mean +/- SD). This was significantly lower than in the normal subjects where it was 5.15 +/- 1.50 l/h (mean +/- SD) (P less than or equal to 0.001).     

Disposition of procainamide and N-acetylprocainamide in protein-calorie malnutrition

The influence of dietary protein deficiency on the disposition of procainamide (PA) and its major metabolite, N-acetylprocainamide (NAPA) was investigated in male Sprague-Dawley rats fed for 4 weeks on a 23 (control) or a 5% (low) protein diet ad libitum. Procainamide and N-acetylprocainamide in plasma and urine were determined by a sensitive and specific HPLC assay using a cation-exchange column. After an iv dose of 50 mg/kg procainamide hydrochloride, the average mean residence time (MRT) was approximately 82% higher, while the total plasma clearance (CI) per kg of body weight and terminal elimination rate constant (k) were significantly decreased by 46 and 49%, respectively, in the protein-deficient animals. No significant differences were found in the two groups of animals with respect to the apparent steady state volume of distribution (Vss). Although the percentage of PA recovered unchanged in the urine over 48 hr was not significantly different between control and protein-deficient animals, rats on a low protein diet excreted a smaller percentage of the administered PA dose (mean +/- SE, 19.0 +/- 4.0 vs. 30.8 +/- 1.4%) as NAPA. In addition to the apparent decrease in metabolic clearance (CIm) to NAPA (6.8 +/- 1.4 vs. 19.9 +/- 2.3 ml/min/kg) in the protein-deficient rats, there was a 55% decrease in the renal clearance of PA. There appeared to be no significant difference in the disposition characteristics of NAPA (i.e. MRT, Vss, CI, and k) between the two groups of animals after a 25 mg/kg dose of N-acetylprocainamide hydrochloride.(ABSTRACT TRUNCATED AT 250 WORDS)     

Influence of hepatic regeneration after partial hepatectomy on theophylline pharmacokinetics in rats.

The influence of hepatic regeneration after partial hepatectomy on theophylline pharmacokinetics has been studied on the rat. At different times after partial hepatectomy, theophylline was administered intravenously as a single dose of 6 mg/Kg. Drug plasma levels were determined by HPLC and pharmacokinetic parameters were obtained. Physiological parameters were also measured. Following hepatectomy, an increase in mass liver was observed and 15 days after surgery, liver mass was 78% of nonhepatectomized rats. Initial theophylline concentrations varied during the regeneration period, as well as the distribution volume at steady-estate (Vss). Elimination half-life (t 1/2), notably increased after hepatectomy (7.27+/-1.38 h), decreased with time (6.70+/-1.18 h, 6.47+/-0.69 and 5.17+/-0.87 h after 24 h, 3 days and 15 days post-hepatectomy, respectively) to reach a value close to that of the control group (4.30+/-1.37 h). The increase in elimination half-life led to a decrease in the mean residence time during the period of liver regeneration. However, the intrinsic clearance hardly varied during regeneration period. We could establish the following relationship between liver weight (LW) and the elimination half-life: t 1/2 (h)=-0.358*LW (g)+8.6168 (R2=0.9906). For the mean residence time (MRT) this relationship was: MRT (h) =-0.5173*LW (g)+12.433 (R2=0.991).     

Absolute bioavailability and noncompartmental analysis of intravenous and intramuscular Cefotan (cefotetan) in normal volunteers

Cefotetan (1 g) was administered to 12 normal volunteers as a 30 minute intravenous infusion and as an intramuscular injection. The pharmacokinetic parameters were estimated using noncompartmental analysis. The mean +/- SD maximum plasma concentration, terminal half-life, and systemic clearance after intravenous infusion were 158 +/- 21 micrograms/mL, 4.54 +/- 1.05 hours, and 29.1 +/- 3.8 mL/min/1.73 m2, respectively. Renal clearance and nonrenal clearance accounted for 63.1% and 36.9% of the systemic clearance, respectively. The mean +/- SD maximum plasma concentration, time to maximum concentration, terminal half-life, and absolute bioavailability after intramuscular injection were 75.5 +/- 8.7 micrograms/mL, 1.33 +/- 0.48 hours, 4.32 +/- 0.77 hours, and 0.931 +/- 0.193, respectively. Moment analysis gave average +/- SD mean residence times (MRT) of 4.98 +/- 0.75 and 5.86 +/- 0.77 hours after intravenous and intramuscular administration, respectively. The average +/- SD mean absorption time (MAT) after intramuscular injection was 1.11 +/- 0.57 hours. The mean +/- SD steady-state volume of distribution after intravenous infusion was 0.129 +/- 0.024 L/kg. The mean +/- SD cumulative percentage of the dose excreted in the urine in 24 hours were 61.1 +/- 11.4% and 50.4 +/- 13.5% after intravenous and intramuscular dosing, respectively. The maximum urinary cefotetan concentrations occurred during the first 2 hours after dosing by both routes of administration. Cefotetan tautomer was detected in the plasma and urine of all subjects after both routes of administration, but the mean concentrations were only minimal compared to those for cefotetan. In conclusion, intramuscular cefotetan (1 g) is rapidly and almost completely absorbed.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetics of vancomycin administered as prophylaxis before cardiac surgery

Vancomycin concentrations in serum, tissues, and sternum, administered as prophylaxis to patients during coronary artery bypass surgery, were measured. Vancomycin (15 mg/kg) was administered to 15 patients 1 hour before skin incision. Blood, tissue, and sternum samples were collected before, during, and after bypass. The concentration in serum at the end of infusion was 55.1 +/- 22.8 microg/mL, the mean elimination half-life was 9 +/- 4 hours, the areas under the concentration-time curve (AUC) from 0 to 12 hours and from 0 to infinity were 90.6 +/- 25.1 and 289.7 +/- 86.5 microg/h per mL, respectively, the mean residence time (MRT) was 11.9 +/- 5.0 hours, the mean volume of distribution was 51.1 +/- 12.2 L, and the total clearance was 78.3 +/- 32.6 mL/min. Vancomycin concentrations in serum, tissues, and sternum during the operation were greater than the MIC90 for most staphylococci and ranged from 16 to 55 microg/mL in serum and from 4 to 39 microg/g in sternum and tissues.     

Effects of chronic amantadine hydrochloride ingestion on its and acetaminophen pharmacokinetics in young adults.

The authors studied the effect of chronic amantadine ingestion on its own disposition and that of acetaminophen in five healthy young adults. The half-life of amantadine after 42 days ingestion was 15.1 +/- 2.3 hours and was not different from 14.8 +/- 4.4 hours after an acute ingestion (mean +/- SD). However, chronic amantadine ingestion was associated with an increased apparent volume of distribution for acetaminophen, 1.1 +/- 0.1 L/kg compared with 0.9 +/- 0.1 L/kg, when the two drugs were concurrently ingested after a 2-week washout period. This difference in kinetic distribution was not reflected in terminal acetaminophen half-life, 149 +/- 54 versus 151 +/- 55 minutes for chronic and acute amantadine ingestion, respectively. Plasma acetaminophen clearance with chronic amantadine ingestion (5.8 +/- 2.6 mL/min/kg) was not different from that determined after acute coingestion of both drugs (4.3 +/- 1.1 mL/min/kg). Thus, no change in recommended dose is necessary when these two drugs are coingested.     

Effect of severe renal failure and haemodialysis on the pharmacokinetics of levosimendan and its metabolites

BACKGROUND AND OBJECTIVES: Levosimendan is a calcium sensitiser developed for the treatment of congestive heart failure. It increases myocardial contractility, reduces the filling pressure and dilates both the peripheral and coronary vessels. The circulating metabolites of levosimendan, OR-1855 and OR-1896, are formed and eliminated slowly after intravenous administration of levosimendan. The aim of this study was to investigate the effect of impaired renal function and haemodialysis on the pharmacokinetics of levosimendan, OR-1855 and OR-1896. STUDY DESIGN: This study was an open-label, nonrandomised, phase I pharmacokinetic study. Levosimendan was administered as a single-dose infusion of 0.1 microg/kg/minute for 24 hours. The follow-up period lasted 3 weeks. STUDY SETTING: Twenty-fivepatients were included:12 patients with severe chronic renal failure (CRF) with creatinine clearance of < 30 mL/minute/1.73 m(2) and 13 patients with end-stage renal disease (ESRD) undergoing haemodialysis. A group of 12 healthy subjects served as controls. RESULTS: Levosimendan, the parent drug, was eliminated rapidly from the plasma after discontinuation of its infusion, with an elimination half-life (t(1/2)) [mean +/- standard error of mean] of 1.5 +/- 0.09 hours in ESRD patients undergoing haemodialysis, 1.0 +/- 0.2 hours in patients with severe CRF and 0.91 +/- 0.03 hours in healthy subjects. The t(1/2) of levosimendan was significantly longer (p < 0.001) in ESRD patients undergoing haemodialysis than in healthy subjects. The t(1/2) of OR-1855 and OR-1896 were 94.0 +/- 20.4 hours and 96.5 +/- 19.5 hours, respectively, in ESRD patients undergoing haemodialysis compared with 60.8 +/- 5.2 and 61.6 +/- 5.2 hours, respectively, in healthy subjects (p = not significant). The t(1/2) of OR-1855 was significantly longer (85.0 +/- 13.6 hours) in patients with severe CRF than in healthy subjects (60.8 +/- 5.2 hours, p < 0.05). The area under the plasma concentration-time curve (AUC) and the peak plasma concentration (C(max)) of the metabolites were approximately 2-fold in patients with ESRD undergoing haemodialysis and patients with severe CRF compared with healthy subjects. The mean unbound fraction (f(u)) of levosimendan in plasma was approximately 2% in each study group, whereas the f(u) of the metabolites was considerably higher (63-70%). In contrast to levosimendan, the metabolites were dialysable, with dialysis clearance of approximately 100 mL/minute. The haemodynamic responses and adverse event profiles were similar in the study groups, with headache, palpitations and dizziness being the most frequently recorded adverse events. CONCLUSION: The t(1/2) of the levosimendan metabolites was prolonged 1.5-fold and their AUC and C(max) were 2-fold in patients with severe CRF and ESRD patients undergoing haemodialysis as compared with healthy subjects. These results suggest that the dose should be reduced when levosimendan is used for the treatment of congestive heart failure in patients with severe renal insufficiency.     

The pharmacokinetics of [3H]1-[1-(2-thienyl)cyclohexyl]piperidine (TCP) in Sprague-Dawley rats

Using adult male Sprague-Dawley rats, we examined the blood protein binding and pharmacokinetics of the potent phencyclidine (PCP) receptor ligand 1-[1-(2-thienyl)cyclohexyl]piperidine (TCP). The average percentage of unbound [3H]TCP in rat serum was 42 +/- 6% and the [3H]TCP blood to plasma ratio was 0.98 +/- 0.03 (mean +/- SD, n = 5 in both studies). For the pharmacokinetic studies, [3H]TCP and 1 mg/kg unlabeled TCP were administered as an iv bolus dose. The average [3H]TCP elimination half-life was 2.1 hr. In contrast, total radioactivity in the plasma had a much longer half-life, suggesting much slower metabolite elimination. The average distribution volumes were 27 +/- 17, 15.6 +/- 6.2, and 5.6 +/- 3.0 liters/kg for V beta, Vss, and Vc, respectively. Total body and renal clearance values were 132 +/- 45 and 1.1 +/- 0.4 ml/min/kg, respectively. When TCP pharmacokinetic parameters were compared to PCP pharmacokinetic data in rats from a previous study, a strikingly similar pharmacokinetic profile was found. These data indicated that TCP and PCP are equivalent, from a pharmacokinetic point of view, and that the higher pharmacological potency of TCP over PCP is probably due to receptor-mediated differences.     

Alprazolam kinetics in patients with renal insufficiency

Alprazolam kinetics following a single 1.0-mg oral dose of alprazolam were compared between seven dialysis-dependent patients with chronic renal failure and seven healthy controls matched for age, sex, and weight. There were no significant differences between patients and controls in alprazolam half-life (11.5 vs. 11.3 hours) or clearance of total drug (1.14 vs. 1.26 ml/min/kg). However, alprazolam free fraction was increased in renal failure patients (35.7% vs. 31.9% unbound, p less than 0.005). Free clearance of alprazolam averaged 23% lower in patients (3.2 vs. 4.1 ml/min/kg), but the difference was not significant. Renal insufficiency has a quantitatively small influence on alprazolam pharmacokinetics.     

Single-dose and steady-state pharmacokinetics of tomoxetine in normal subjects

A pharmacokinetic profile of tomoxetine, a selective norepinephrine uptake inhibitor, was developed in human volunteers following single and multiple oral administrations. Following the administration of a single 90-mg oral dose of tomoxetine to four normal volunteers, the plasma half-life was 4.3 +/- 0.5 hours. Mean plasma clearance was 0.60 +/- 0.14 L/Kg/hr, and the mean volume of distribution was 3.7 +/- 0.9 L/kg. Multiple doses of tomoxetine (20 mg bid and 40 mg bid) for seven days were administered to an additional seven subjects. The data appeared to have a bimodal distribution. The mean plasma half-life determined following the last dose was 4.6 +/- 0.5 hours in five subjects. The other two subjects, one at each dose level, demonstrated accumulation of tomoxetine occurring from the first to last dose where tomoxetine disappeared from plasma with a mean half-life of 19 hours.     

Pharmacokinetics of flobufen and its main active metabolite in the rat

Pharmacokinetic study of the anti-inflammatory [3H] flobufen (I) and its active metabolite (II) has been carried out in rats given po and iv doses of 2, 10, and 50 mg/kg I and equimolar doses of II. Various pharmacokinetic parameters of I and II [dose normalized AUC; mean residence time (MRT); systemic blood clearance; steady state volume of distribution, (Vss)] are dose-independent. I is completely absorbed from the gastrointestinal tract and is rapidly (MRT = 7.2 hr) converted to II, which is slowly (MRT = 2.6 days) eliminated from the blood. The fraction of total blood clearance that forms II is 0.83 following iv dose of I. The Vss of the less lipophilic metabolite II is somewhat lower (0.36-0.46 liters/kg) than that of the parent drug (0.51-0.56 liters/kg).     

Pharmacokinetics of lithium in the elderly

The disposition and elimination of lithium was examined in nine female geriatric patients (aged 67 to 80 years) maintained on lithium carbonate as a once daily dose (300 to 600 mg) for the treatment of recurrent depression. Following the morning lithium dose (0.21 +/- 0.06 mmol/kg/day, mean +/- standard deviation), a peak steady state serum concentration of 0.83 +/- 0.25 mmol/liter was achieved at 2.2 +/- 1.2 hours. The mean distribution half-life (alpha-t1/2) was 2.7 +/- 1.2 hours, with distribution being complete at 10.6 +/- 3.0 hours. The mean terminal elimination half-life (beta-t1/2), the mean apparent oral clearance (Cl), and the mean apparent volume of distribution (Varea) were 26.9 +/- 5.5 hours, 15.6 +/- 4.0 ml/min, and 0.64 +/- 0.16 liter/kg, respectively. Compared to a younger adult cohort (35 +/- 10 years), the lithium Cl and Varea were significantly reduced and the alpha- but not beta-t1/2 prolonged in the elderly (p less than 0.05). Based on these pharmacokinetic differences, geriatric patients may require one-third to one-half less lithium than younger adults. The 12-hour standard serum lithium concentration remained a value of minimal intersubject variability when lithium was administered once daily. However, the therapeutic concentration range based on this 12-hour standard serum lithium concentration needs to be redefined for the prophylaxis of unipolar disorders in the elderly.     

Absorption characteristics of sustained-release 4-aminopyridine (fampridine SR) in patients with chronic spinal cord injury

Fampridine SR (4-aminopyridine) is a potassium channel-blocking drug currently being investigated for its therapeutic efficacy in ameliorating central conduction deficits due to demyelination in patients with spinal cord injury (SCI). The present open-label pharmacokinetic trial examined the absorption characteristics of a sustained-release form of the drug in 25 SCI subjects with chronic incomplete injuries. The overall group mean Cmax of 27.7 +/- 6.2 ng/mL occurred at a tmax of 3.4 +/- 1.4 hours. AUC0-12 was 210.5 +/- 49.5 ng/mL.h. For paraplegics, AUCtmax was 76.02 +/- 33.28 and for tetraplegics was significantly less at 51.25 +/- 20.36 (p = 0.037). A statistically significant difference in the initial rate and extent of absorption, but not in total 4-AP bioavailability over the 12-hour study period, was evident between tetraplegic patients, 0.60 +/- 0.23, and paraplegic patients, 0.39 +/- 0.14 (p = 0.02). There was a linear correlation (p < 0.05) between the neurological level of injury and Cmax/AUCtmax. These results confirm and extend previous observations of different rates of drug absorption among SCI patients with lesions above and below the sympathetic outflow (T6) and provide evidence of the absorption characteristics of this sustained-release form of 4-aminopyridine, which is helpful for optimal dosing.     

Comparative pharmacokinetics of intravenous propranolol in obese and normal volunteers

Plasma pharmacokinetics of a single IV dl-propranolol dose (8 mg) were investigated in 12 obese subjects (mean +/- SD: 110.3 +/- 20.4 kg; 198.7 +/- 32.5% of ideal body weight) and compared with those of 12 healthy subjects (66.7 +/- 6.8 kg; 94.5 +/- 7.8% of ideal body weight). In obese subjects plasma alpha-1 glycoprotein acid concentrations and propranolol protein binding capacity did not differ significantly from control subjects. When compared with controls, obese subjects showed a significant increase (P less than .01) in AUC (161.0 +/- 67.0 vs 109.6 +/- 23.1 hr.micrograms/L), and significant decreases (P less than .01) in Vss (208.9 +/- 71.9 vs 318.6 +/- 91.8 L), V beta (234.3 +/- 70.4 vs 340.7 +/- 89.1 L), and total clearance (57.5 +/- 18.3 vs 75.9 +/- 15.4 L/hr). Elimination half-life was similar for the two populations (3.5 +/- 0.9 hr in obese subjects vs 3.1 +/- 0.9 hr in controls). Therefore, neither lipophilicity of propranolol nor drug plasma protein binding can explain these data. Altered hepatic function and tissue blood flow in obese subjects are proposed as an explanation for the decrease in total clearance and volume of distribution.     

The pharmacokinetics of dexfenfluramine in obese and non-obese subjects.

The pharmacokinetics of dexfenfluramine (d-F) and its metabolite dexnorfenfluramine (d-NF) were compared in 10 obese (145 +/- 13 s.d. % of ideal body weight (IBW)) and 10 non-obese healthy volunteers (93 +/- 8% IBW). Each group included five men and five women, aged 28 +/- 8 years. Subjects were given single doses of d-F i.v. (15.5 mg base infused over 3 h) and orally (25.9 mg base in capsules) on separate occasions. After i.v. infusion in obese subjects, the volume of distribution (Vss) of d-F was significantly higher (969.7 +/- 393.3 l; 95% CI 688.6-1250 l) than in controls (668.7 +/- 139.6 l; 95% CI 568.9-768.5 l; P < 0.01). Clearance was not significantly different (43.9 +/- 21.0 l h-1 vs 37.3 +/- 10.6 l h-1) and the terminal half-life tended to be longer (17.8 +/- 9.4 vs 13.5 +/- 3.9 h NS). Combined data from the two groups indicated a positive correlation between Vss and % IBW (r = 0.544; P < 0.02). The oral bioavailability of d-F was 0.61 +/- 0.15 in obese subjects and 0.69 +/- 0.11 in controls. There was no significant difference between obese subjects and controls in Cmax, tmax and t1/2,z (Cmax: 20.1 +/- 6.7 and 27.3 +/- 6.2 micrograms l-1; tmax: 3.5 vs 3.0; t1/2,z: 16.5 +/- 7.1 vs 14.5 +/- 2.6 h respectively). The AUC ratio expressed in molar units for d-F/d-NF was 2.29 +/- 1.78 (i.v.) vs 1.25 +/- 0.64 (oral) in obese subjects and 2.05 +/- 1.26 (i.v.) vs 1.40 +/- 0.87 (oral) in controls.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetics of ceftriaxone in liver-transplant recipients

The disposition of ceftriaxone was studied after a single 2 g intravenous dose in seven patients 3 to 5 days after liver transplantation. Ceftriaxone concentrations in plasma, urine, and bile were measured by HPLC, and plasma protein binding was determined by equilibrium dialysis. Plasma protein binding was nonlinear, and the unbound fraction varied between 0.05 and 0.56. Both capacity and affinity were markedly different from reported values for normal subjects. The pharmacokinetic parameters obtained were: total body clearance (TBC), 11.2 +/- 7.8 mL/hr/kg total and 44.8 +/- 29.1 mL/hr/kg unbound; volume of distribution (V(area)), 224 +/- 76 mL/kg total and 767 +/- 432 mL/kg unbound; steady-state volume of distribution (Vss), 212 +/- 68 mL/kg total and 651 +/- 368 mL/kg unbound; terminal disposition half-life (t1/2), 21.6 +/- 14.3 hour total and 16.3 +/- 11.1 hour unbound. TBC for both total and free drug was considerably lower than literature values for normal subjects. V(area) for total drug was greater than normal, whereas the corresponding value for free drug was smaller than normal. The plasma ceftriaxone concentrations at 12 and 24 hours were above the reported minimum inhibitory concentration (MIC). The fraction of the administered dose excreted in urine over 24 hours was 38 +/- 29% and did not differ markedly from that reported for normal subjects. Less than 2% of the administered dose was excreted in 24-hour bile; however, biliary concentrations were always above MIC. Ceftriaxone can be administered once or twice daily at a dose of 2 g/day for prophylaxis in liver transplant recipients.