Metabolism and pharmacokinetics of dothiepin.

1 Seven healthy volunteers received a single oral dose of 75 mg dothiepin. Plasma concentrations of dothiepin were measured by gas chromatography-mass fragmentography. 2 The plasma concentrations obtained were fitted to the equation Ct = Ae-a(t-tau) + Be-beta(t-tau) - Ce-ka(t-tau). The mean peak concentration was 47(33-71) microgram/l at 3(2-5) h. Mean estimates were as follows: absorption half life 1.2(0.07-3.0) h, distribution half-life 2.6(1.1-3.8) h, elimination half-life 22(14-40) h, apparent volume of distribution 45(20-92) l/kg, and oral clearance 1.36(0.88-1.8) l kg-1 h-1. 3 Blood concentrations of dothiepin were measured in comparison in five of the volunteers. The mean blood/plasma ratio was 0.7(0.6-0.8). 4 Plasma and blood concentrations of northiaden and blood concentrations of dothiepin S-oxide, two metabolites of dothiepin, were also measured. Dothiepin S-oxide was the major metabolic reaching a peak level of 81(34-150) microgram/l at 5(4-6) h. In comparison, northiaden reached a peak concentration of only 10 (3-21) microgram/l at 5 (4-9) h. The mean half-life of elimination of dothiepin S-oxide was 19 (13-35) h while that for northiaden was 33 (22-60) h.     

Pharmacokinetics of intravenous bepridil in patients with coronary disease

The pharmacokinetics of intravenous bepridil (1-[2-(N-benzylanilino)-1-(isobutoxymethyl)ethyl]pyrrolidine ) were studied in 16 patients undergoing cardiac catheterization for evaluation of coronary disease, all with normal base-line hemodynamic and renal functions. Ten patients received 3 mg/kg and six patients received 4 mg/kg of bepridil infused over a period of 30 min. Plasma bepridil concentrations were measured by HPLC and analyzed by model-dependent and model-independent methods. The mean (+/- SD) maximum plasma bepridil concentrations at the end of the infusion were 2047 +/- 820 ng/mL (3 mg/kg) and 2478 +/- 1426 ng/mL (4 mg/kg). Postinfusion bepridil concentrations were best described by a two-compartment open model. The model-dependent harmonic mean distribution and elimination half-lives were 1.7 h (range: 1.1-2.2 h) and 19.7 h (range: 8.0-61.9 h), respectively. The harmonic mean elimination half-life from model-independent analysis was 14.9 h (range: 7.4-64.0 h). The arithmetic means of other model-independent kinetic parameters were systemic clearance, 0.524 +/- 0.215 L X kg-1 X h-1; Vd, 15.3 +/- 10.9 L/kg; and Vdss, 10.1 +/- 6.0 L/kg. Model-dependent and model-independent estimates of half-life and clearance agreed reasonably well. Bepridil was well tolerated, effecting little or no change in central hemodynamics or EKG intervals. The extensive distribution and relatively slow clearance of bepridil account for its long elimination half-life. Intravenous bepridil appears to be a safe calcium (II) antagonist that is suitable for once-a-day dosing.     

Effect of polymorphic CYP3A5 genotype on the single-dose simvastatin pharmacokinetics in healthy subjects

Simvastatin, a cholesterol-lowering agent, is mainly metabolized by CYP3A4/5. The objective of this study was to investigate the effect of CYP3A5*3 genotype on the pharmacokinetics of simvastatin in humans. Twenty-two men with CYP3A5*1/*1 (n = 4), CYP3A5*1/*3 (n = 8), or CYP3A5*3/*3 (n = 10) genotypes were enrolled. Each subject ingested a 20-mg dose of simvastatin, and plasma simvastatin concentrations were measured for 12 hours after dosing. The mean (+/-SD) area under the plasma concentration-time curve for simvastatin in the CYP3A5*1/*1 carriers (4.94 +/- 2.25 ng x h/mL) was significantly lower than CYP3A5*3/*3 carriers (16.35 +/- 6.37 ng x h/mL; P = .013, Bonferroni test). The mean (+/-SD) oral clearance was also significantly different between CYP3A5*1/*1 carriers (4.80 +/- 2.35 L/h) and CYP3A5*3/*3 carriers (1.35 +/- 0.61 L/h; P < .05, Dunn's test). However, other pharmacokinetic parameters including peak plasma concentrations and half-life did not show any difference between genotype groups. These findings suggest that the polymorphic CYP3A5 gene affects the disposition of simvastatin and provides a plausible explanation for interindividual variability of simvastatin disposition.     

Pharmacokinetics of mitoxantrone in patients after 2 h and 24 h intra-arterial administration

The pharmacokinetic parameters of mitoxantrone in patients with liver metastasis after intra-arterial 2 h and 24 h infusion (dosage 12 mg/m2) were investigated. Peak plasma concentrations were 305 +/- 60 ng/ml at 2 h infusion and 244 +/- 89 ng/ml at 24 h infusion. These peak plasma concentrations occurred at 0.9 +/- 0.8 h during 2 h infusion and 5.5 +/- 3.4 h during 24 h infusion. No significant difference between both intra-arterial administrations in elimination half-life (50-223 h at 2 h infusion, 58-246 h at 24 h infusion) and area under the plasma concentration-time curve (AUC0-72 = 11.6 micrograms/ml.h for 2 h infusion, AUC0-72 = 11.2 micrograms/ml.h for 24 h infusion) could be found. The results indicate that no change of availability in the central compartment at infusion of mitoxantrone over a period of 24 h could be achieved. The 2 h infusion lead to sufficient plasma levels with pharmacokinetic parameters of mitoxantrone similar to 24 h infusion and showed a good clinical picture with mild toxicity.     

Pharmacokinetics of oral pramiracetam in normal volunteers

The pharmacokinetics of pramiracetam, a new, investigational, cognition activator, were assessed in normal male volunteers as part of a clinical tolerance study. In a double-blind, randomized design, two groups of six subjects each received alternating placebo and single 400, 800, 1,200, and 1,600 mg oral doses of pramiracetam after an overnight fast. Mean (+/- SD) peak plasma concentrations of the four dose groups (2.71 +/- 0.54, 5.40 +/- 1.34, 6.13 +/- 0.71, 8.98 +/- 0.71 micrograms/mL) were attained between two to three hours following drug administration. The harmonic mean elimination half-life (4.5-6.5 hours), the mean total body clearance (4.45-4.85 mL/min/kg), the mean renal clearance (1.83-3.00 mL/min/kg), and the mean apparent volume of distribution (1.82-2.94 L/kg) were independent of dose, whereas the peak plasma concentrations and area under the curves increased as a linear function of dose. No significant side effects were observed at any dose level.     

Bayesian pharmacokinetics of gentamicin in a haemodialysis population

BACKGROUND: Aminoglycosides are commonly used in the haemodialysis population. Standard pharmacokinetic approaches require multiple sampling to describe the parameters of drug distribution and elimination in the intra- and interdialytic periods. OBJECTIVE: To characterise the pharmacokinetics of gentamicin in a haemodialysis population by using Bayesian pharmacokinetic methods and only two plasma concentrations. DESIGN AND PARTICIPANTS: Prospective case series of 13 adult (aged 36-70 years) haemodialysis patients (Fresenius F80 dialysers were used) receiving gentamicin. METHODS: Patients with suspected or confirmed Gram-negative infections were given gentamicin. At 48 hours after receiving the dose (at the next haemodialysis session), patients provided two blood samples, one immediately before the dialysis session and another 1 hour after haemodialysis. Data on dosage, timing and plasma concentrations for all subjects were analysed with PASTRX version 10.6 and Bayesian pharmacokinetic analysis. Volume of distribution (Vd), interdialytic elimination rate constant (k(inter)), interdialytic elimination half-life (t1/2beta, inter)) and interdialytic clearance (CL(inter)) were determined from a single predialysis plasma concentration. Elimination rate constant (k(dial)), elimination half-life (t1/2beta, dial)) and clearance (CL(dial)) during 3.5-4 hours of dialysis were also determined from the pre- and post-plasma concentrations. RESULTS: Pharmacokinetic parameters (mean +/- SD) were: Vd 0.288 +/- 0.002 L/kg, k(inter) 0.015 +/- 0.004h(-1), t1/2beta, inter) 48 +/- 11h, CL(inter) 5.9 +/- 2.4 mL/min, k(dial) 0.25 +/- 0.05 h(-1), t1/2beta, dial) 3.0 +/- 1.0h and CL(dial) 91 +/- 24 mL/min. CONCLUSIONS: The rate of elimination of gentamicin was 17-fold greater (95% CI 13.7-20.7) on haemodialysis with a Fresenius F80 than off haemodialysis. All of the pharmacokinetic parameters of interest were determined using Bayesian pharmacokinetic procedures and only two plasma gentamicin concentrations.     

Experience with a computer-based technique for estimating pharmacokinetic constants from limited data

A computer-based approach for estimating pharmacokinetic data and predicting plasma drug concentrations based on two measurements of plasma drug concentrations was compared with a standard two-point method for estimating aminoglycoside (AG) pharmacokinetic parameters. The computer-based technique was also used to predict a theophylline steady-state nadir from two preceding ones. The computer-based and standard two-point methods provided similar estimates for mean (+/- SD) values of elimination rate constant (lambda) (0.172 +/- 0.103 h-1 and 0.179 +/- 0.010 h-1, respectively) and apparent volume of distribution (V) (22.7 +/- 9.9 L and 23.3 +/- 11.5 L, respectively). The mean (+/- SD) of predicted AG troughs was 1.3 +/- 0.5 mg/L for the standard method and 1.3 +/- 0.6 mg/L for the computer-based method. Neither was significantly different from the actual AG trough mean of 1.3 +/- 0.7 mg/L. Both methods exhibited a slightly negative bias in their predictions of actual AG troughs. When applied to theophylline data from patients or subjects receiving multiple-dose theophylline, the computer-based method effectively predicted trough theophylline concentrations for three formulations of theophylline. Mean prediction errors ranged from 0.1 to 0.5 mg/L, and root mean squared error ranged from 1.1 to 1.2 mg/L. This computer-based technique may be useful in dose individualization since relatively few constraints are placed on the type of data required for its application.     

Disposition of dothiepin after overdose: effects of repeated-dose activated charcoal.

Although the tricyclic antidepressant dothiepin is often encountered in deliberate self-poisonings, there are no published studies of its disposition in overdose. In the present study, we have documented the plasma disposition of dothiepin and its major metabolites in eight overdose patients. All had high initial levels of dothiepin (819-3,851 micrograms/L), dothiepin-S-oxide (655-2,162 micrograms/L), nordothiepin (88-422 micrograms/L), and nordothiepin-S-oxide (176-530 micrograms/L) that were considerably above steady-state therapeutic concentrations. In three patients who received treatment with repeated-dose activated charcoal, dothiepin half-lives were 10.6, 12.5, and 13.1 h compared with the literature range of 18.5-24 h. All patients survived and none experienced any significant cardiovascular event despite exhibiting clinical signs of tricyclic antidepressant overdose. We suggest that repeated-dose activated charcoal treatment may decrease the dothiepin half-life after overdose.     

No correlations between the urinary ratio of 6beta-hydroxycortisol to free cortisol and pharmacokinetics of alprazolam

OBJECTIVE: The urinary ratio of 6beta-hydroxycortisol to cortisol is known as a possible marker of CYP3A4 activity. We investigated the correlation between this ratio and the disposition of alprazolam, which is a substrate of CYP3A4. METHODS: Twelve healthy volunteers took a single dose (0.8 mg) of alprazolam at 0800 hours. Blood samplings were conducted up to 48 h after the dosing. Urine was collected during the 24 h prior to dosing. Quantification of alprazolam in plasma and that of cortisol and 6beta-hydroxycortisol in urine was performed using high-performance liquid chromatography. RESULTS: Mean (+/-SD) values of peak plasma concentration (Cmax), time to Cmax (tmax), area under the plasma concentration-time curve [AUC(0-48)] and elimination half-life (tl/2) of alprazolam were 12.0+/-3.0 ng/ml, 1.5+/-0.9 h, 200+/-41 ng/ml h and 16.0+/-4.3 h, respectively. Mean (+/-SD) urinary ratio of 6beta-hydroxycortisol to cortisol was 3.28+/-0.67. No significant correlations were found between urinary ratio of 6beta-hydroxycortisol to cortisol and any pharmacokinetic parameters of alprazolam (Cmax: rs= -0.06; tmax: r(s)= 0.34; AUC(0-48): rs=0.08; t1/2: r(s)= -0.36). CONCLUSION: This study suggests that the urinary ratio of 6beta-hydroxycortisol to cortisol is unlikely to predict pharmacokinetics of alprazolam.     

Pharmacokinetics of primaquine in man. II. Comparison of acute vs chronic dosage in Thai subjects.

We have investigated the pharmacokinetics of primaquine after acute and chronic administration of the drug to five healthy Thai volunteers. After acute dosage (15 mg p.o.) mean (+/- s.d.) peak plasma concentrations of 65.0 +/- 34.7 ng ml-1 were achieved within 2 +/- 1h. Thereafter plasma drug concentrations declined monoexponentially with a mean elimination half life of 4.4 +/- 1.4 h. The mean (+/- s.d.) oral clearance was 37.6 +/- 15.5 1 h-1. These values are in broad agreement with values obtained in healthy Caucasians after administration of an equivalent dose of primaquine. Repeated dosing with primaquine had no effect on the mean pharmacokinetic parameters calculated for this drug. In contrast, individual pharmacokinetic parameters for some subjects exhibited gross and unpredictable changes after chronic dosage. The carboxylic acid metabolite of primaquine accumulated in plasma after repeated dosing such that by day 14 of chronic dosing the mean AUC (0,24) for this metabolite was 74% greater than that obtained after acute administration of primaquine.     

Pharmacokinetics of diminazene in sheep

The pharmacokinetic behavior of diminazene in plasma after administration of 2 mg/kg i.v. and 3.5 mg/kg i.m. was studied in four healthy Dala x Ryggja rams. Following i.v. injection, the data were satisfactorily described by a tri-exponential equation; the apparent volume of distribution at the steady-state was 0.56 +/- 0.04 L/Kg (mean +/- SD; n = 4); total body clearance averaged 1.1 +/- 0.09 ml/kg/min and elimination half-life was 9.30 +/- 1.40 hr. After intramuscular administration peak plasma levels of 6.30-7.57 micrograms/ml were reached in 20 to 45 min and the mean absorption time averaged 5.83 +/- 1.61 hr. Systemic availability relative to the intravenous dose was 95.10 +/- 23.21% and mean residence time averaged 14.16 +/- 1.55 hr. The partition of diminazene between erythrocytes and plasma averaged 0.64 +/- 0.10; plasma protein binding was high (65-85%) and concentration-dependent. Based on the experimental data obtained, an initial i.m. dose of 2.5 mg/kg followed by 2 mg/kg 24 hr later should be safe and effective in cases of babesiosis and trypanosomiasis sensitive to diminazene. A preslaughter withdrawal period of 14-26 days was estimated.     

Amoxicillin pharmacokinetics in (preterm) infants aged 10 to 52 days: effect of postnatal age

The pharmacokinetic parameters of amoxicillin were determined in 32 newborn infants aged 10 to 52 days (mean postnatal age, 24.7 +/- 12.4 days) to improve amoxicillin dosing in this age group. Amoxicillin plasma concentrations were determined using reversed-phase high-performance liquid chromatography in surplus plasma samples from routine gentamicin assays. Amoxicillin pharmacokinetic parameters (mean +/- SD) were as follows: first-order elimination constant (K(el)) = 0.27 +/- 0.10 h(-1), volume of distribution corrected for body weight (V/W) = 0.66 +/- 0.27 L/kg, total body clearance corrected for body weight (CL/W) = 0.18 +/- 0.10 Lkg(-1)h(-1), and elimination half-life (t(1/2)) = 3.0 +/- 1.3 hours. Amoxicillin body clearance was approximately twofold greater in our patients compared with published values in younger neonates (mean postnatal age, 0.76 +/- 1.57 days). Simulation studies using the observed amoxicillin pharmacokinetic data suggest an amoxicillin dose of 40 mg/kg administered every 8 hours in infants older than 9 days postnatal age, independent of gestational age and postconceptional age, to achieve satisfactory target plasma amoxicillin concentrations less than 140 mg/L and time above minimum inhibitory concentration of at least 40%. Prospective evaluation of this suggested new dosage regimen is necessary before implementation in the care of ill neonates.     

A large-sample study of diazepam pharmacokinetics

Healthy male volunteers (n = 48) aged 18-44 years received a single 10-mg oral dose of diazepam. Plasma diazepam and desmethyldiazepam concentrations were measured at multiple points during the next 11 days. The distribution of peak plasma concentration (mean, 406 ng/ml) was not skewed and did not differ significantly from normal (Guassian). However, the distributions of elimination half-life (44.2 h), elimination rate constant (0.0219/h), clearance (26.6 ml/min), and volume of distribution (83 L) all were significantly skewed and deviated significantly fron normal. After logarithmic transformation, the distributions of elimination rate constant, elimination half-life, and volume of distribution were consistent with normal; however, this was not the case for time of peak plasma concentration. Thus, the pharmacokinetic characteristics of oral diazepam are highly variable even in a relatively homogeneous population. Parametric statistical testing procedures and pharmacokinetic forecasting schemes may be improved by more precise delineation of the underlying distributions for pharmacokinetic variables.     

Pharmacokinetics of sulpiride in humans after intravenous and intramuscular administrations.

The pharmacokinetics of sulpiride in plasma, red blood cells (RBC), and urine were investigated after administration of 100 mg by the iv route to 15 subjects and by the im route to 12 subjects. The concentrations of sulpiride in plasma, RBC, and urine were measured by HPLC. All the data were consistent with a two-compartment, open-body model. After iv administration, the mean +/- SD apparent elimination half-life of sulpiride was 6.47 +/- 1.00 h, and the mean +/- SD volume of distribution at steady state was 0.94 +/- 0.23 L/kg. Renal clearance (119.5 +/- 28.2 mL/min) was very close to total clearance (127.8 +/- 26.2 mL/min). In urine, the mean +/- SD recovery in form of the unchanged drug was 90.0 +/- 9.68% of the administered dose, and the excretion rate versus time showed an elimination half-life similar to that found in plasma. The values of all these parameters were very close to those obtained after im administration. The sulpiride partition coefficient between RBC and plasma did not show any significant change as a function of time and concentration, with a mean value +/- SD of 1.00 +/- 0.043, indicating that sulpiride is evenly distributed between RBC and plasma. The pharmacokinetic parameters determined from the plasma and the RBC data were similar.     

Plasma tenoxicam concentrations after single and multiple oral doses

The pharmacokinetics of single- and multiple-dose administration of tenoxicam 20 mg were evaluated in 8 healthy males. Maximum plasma concentration (Cmax) after the first dose was 2.76 +/- 0.48 micrograms/ml (mean +/- s.d.) and the time to reach Cmax (Tmax) was 5.0 +/- 3.0 h. The area under the plasma concentration-time curve (AUC0-infinity) after a single administration of tenoxicam was 242.5 +/- 73.5 micrograms x h/ml. The elimination half-life (t1/2) was 66.3 +/- 15.8 h and the plasma concentration at 24 hours after dosing (Cmin) was 1.84 +/- 0.33 micrograms/ml. Steady-state plasma concentrations of tenoxicam were virtually reached after 10 consecutive daily doses. At steady-state, Cmax averaged 13.63 +/- 3.33 micrograms/ml and Tmax remained 5.0 +/- 3.0 hours. AUC within a dosing interval at steady-state was 262.2 +/- 67.0 micrograms x h/ml, Cminss was 9.67 +/- 3.25 micrograms/ml, and t1/2 averaged 74.2 +/- 13.3 h. The average fluctuation during multiple-dose administration was 26.8 +/- 8.0% and the accumulation ratio was 5.82 +/- 0.60. Steady-state pharmacokinetic parameters predicted from the first-dose data slightly underestimated observed values, but the results supported the assumption of linear pharmacokinetics during multiple-dose tenoxicam administration.     

Comparison of propranolol and sotalol pharmacokinetics in obese subjects

Six obese subjects (mean +/- s.d. : 145.1 +/- 16.7% of ideal body weight) were randomly assigned to a single i.v. dose either of (+/-)-propranolol base (0.108 mg kg-1 of ideal body weight) or of (+/-)-sotalol base (1.06 mg kg-1 of ideal body weight). Each subject received the other drug 7 days later. Pharmacokinetic parameters were compared with those obtained previously in non-obese control subjects. In obese subjects, the pharmacokinetic data calculated for sotalol were comparable with those measured in controls (total body clearance = 9.4 +/- 2.9 L h-1; volume of distribution during the terminal phase = 79.8 +/- 19.8 L or 0.9 +/- 0.2 L kg-1; terminal half-life = 6.2 +/- 1.6 h). For propranolol, total clearance (44.3 +/- 15.9 L h-1) and volume of distribution (230.5 +/- 48.2 L or 2.7 +/- 0.7 L kg-1) were significantly less than control values. The terminal half-life (3.9 +/- 1.1 h), was not significantly increased. These results could be explained by altered tissue blood flow and a decreased metabolic capacity of the liver in obese subjects.     

Plasma and breast milk concentrations of dothiepin and northiaden in lactating women

Plasma and breast-milk concentrations of dothiepin and its metabolite northiaden were measured in 20 lactating women receiving the drug for post-partum depression. Samples were collected at steady-state and both compounds quantitated by HPLC. Doses of dothiepin varied from 75 mg/day to 225 mg/day. Accordingly a wide range of plasma and breast-milk concentrations of dothiepin and northiaden were determined. Most determinations were made for women receiving 150 mg/day. At this dose mean (± SD) plasma concentrations of dothiepin and northiaden were 56(±27)m?g/l and 72(±79)m?g/l respectively while breast-milk concentrations were 95(±71) m?g/l and 40(±29) m?g/l for dothiepin and northiaden respectively. The data reflect the well recognised inter-individual variability in plasma concentrations for subjects receiving the same oral dose. Similar variability was noted in breast-milk concentrations at all doses of dothiepin. Dothiepin passes into the breast-milk of lactating women receiving the drug for post-partum depression. In this respect the drug is similar to other tricyclic antidepressants. The inter-individual variability of results recorded here suggest the need to determine drug concentrations on an individual basis before reaching a decision about breastfeeding. Perceived side effects in the infant are clear criteria for cessation of breastfeeding; high levels of drug in breastmilk where the infant is unaffected, warrant monitoring in view of our inadequate knowledge regarding long term effects of these drugs.     

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.     

Absolute bioavailability of mianserin tablets and solution in healthy humans

A pharmacokinetic study with mianserin . HCl was performed in six healthy male subjects. The subjects were treated on different occasions intravenously with a constant-rate infusion of 5 mg mianserin. HCl in 1 h, orally with a single dose of 60 mg as two tablets of 30 mg each and with 60 mg as an oral solution. The wash-out period between treatments was 1 month. Blood samples were taken at predetermined times over a period of 120 h following dosing. The mianserin concentration in the plasma samples was determined and the results were pharmacokinetically analyzed. The intravenous data could be adequately described by a 3-compartment model and the oral data by a 2-compartment model, both with first-order transfer and elimination rate constants. The mean plasma clearance of mianserin was found to be 19 +/- 2 l h-1 (mean +/- SEM), the kinetic volume of distribution 444 +/- 250 l, the steady-state volume of distribution 242 +/- 171 l and the elimination half-life 33 +/- 5 h. The absolute bioavailability in terms of extent of absorption was 22 +/- 3% for the solution and 20 +/- 3% for the tablets. The mean peak level for the solution was 79 +/- 11 ng X ml-1 and for the tablets 54 +/- 5 ng X ml-1; mean peak time for the solution was 1.1 +/- 0.2 h and for the tablets 1.4 +/- 0.2 h. The mean absorption half-life for the solution was 0.43 +/- 0.13 h and for the tablets 0.39 +/- 0.11 h.(ABSTRACT TRUNCATED AT 250 WORDS)     

Buprenorphine pharmacokinetic parameters during coronary artery bypass graft surgery

The pharmacokinetic parameters of buprenorphine (BN) after a single bolus dose of 10 microg/kg i.v. was investigated in 6 male patients whose age averaged 59+/-9.8 years and body weight of 65.8+/-5.7 kg undergoing coronary artery bypass graft surgery (CABG). The unbound BN plasma concentrations were detected using ultrafiltration and high performance liquid chromatography/electro-chemical detection (HPLC/ECD) method. During cardiopulmonary bypass (CPB) there was a fall in BN plasma concentrations, observations similar to reports on fentanyl, sufentanil and alfentanil. This is probably due to haemodilution, hypothermia and hydrophobic sequestration of drug on to the CPB tubing. After CPB the concentrations rose to values higher than during CPB, though it did not attain pre CPB concentrations. These variations were not statistically significant indicating that plasma levels were adequately stable during CPB. The plasma concentration time curves were biexponential and the pharmacokinetic parameters obtained were : distribution half-life 37.24+/-6.57 min, elimination half-life 482.69+/-79 min, clearance 1221.97+/-209.42 ml/min, and volume of distribution 736.46+/-71.25 L. BN in the dose used follows the pharmacokinetic pattern of other commonly used narcotics during CABG. The mean +/- SEM plasma BN concentration during CPB was 0.51+/-0.03 ng/ml which was adequate for the maintenance of analgesia and anaesthesia, as none of our patients expressed the signs and symptoms of awareness during surgery. Further, unlike the other narcotics muscle rigidity was absent. Thus BN is a safe and good alternative to other narcotics for patients undergoing CABG.