Pharmacokinetics of ornidazole in patients with renal insufficiency; influence of haemodialysis and peritoneal dialysis.

The pharmacokinetics of ornidazole (Tiberal) was studied after intravenous administration of a single 500 mg dose in eight patients with advanced chronic renal failure (ACRF) (creatinine clearance 2-16 ml/min), in seven patients treated by haemodialysis (residual renal creatinine clearance 0-5 ml/min) and in five patients treated by continuous ambulatory peritoneal dialysis (CAPD) (residual renal creatinine clearance 0-6 ml/min). In ACRF patients, the half-life of ornidazole was 10.8 +/- 1.4 h, the total plasma clearance 46.3 +/- 2.3 ml/min and the volume of distribution 0.73 +/- 0.06 l/kg. During haemodialysis, ornidazole was partly removed: the dialyser extraction ratio was 42 +/- 5% and the dialysis clearance 64 +/- 7 ml/min. During CAPD, peritoneal excretion was low: the dialysis clearance was 3.0 +/- 0.4 ml/min and in 48 h 6.0 +/- 1.1% of the administered dose was found in the peritoneal fluids. In these patients, the half-life of ornidazole was 11.8 +/- 0.8 h and total plasma clearance was 48.3 +/- 5.5 ml/min, values which were close to those determined in non dialysed patients. In patients with end-stage renal disease, the half-life of ornidazole is comparable to that of subjects with normal renal function. This is due to the predominantly extra-renal elimination of the drug. Therefore, there is no need to modify the usual dosage of ornidazole for these patients. Because of the large elimination of the drug during haemodialysis it is necessary to administer the drug after the dialysis session.     

Pharmacokinetics of ranitidine after intravenous administration in hemodialysis patients

The pharmacokinetics of ranitidine and its removal by hemodialysis were determined in 9 patients with chronic renal failure requiring hemodialysis. Ranitidine (50 mg) was administered as an intravenous bolus at the beginning of the dialysis procedure, which lasted for 4 h. The elimination half-life, plasma clearance and volume of distribution (VD area) of ranitidine in these patients were 9.0 +/- 2.6 h (mean +/- SD), 305 +/- 152 ml/min and 3.5 +/- 1.9 liters/kg, respectively. About 8% of the administered dose was removed during a single dialysis procedure. The elimination of ranitidine is appreciably reduced in these patients. These results suggest that the dose of ranitidine should be adjusted in patients with severe renal failure who are undergoing hemodialysis, and a suitable schedule for dosing such patients is suggested.     

Pharmacokinetics of postoperative intravenous indomethacin in children

The disposition of indomethacin was studied in children aged one to four years. Indomethacin 0.35 mg/kg was administered as an intravenous infusion during 15 min. Venous blood samples were collected until 24 hr after infusion. Serum indomethacin was determined with gas chromatography. Using a non-linear regression analysis, the individual data were fitted by a two-compartment open mammillary model with central elimination. Calculated pharmacokinetic parameters were (mean +/- SD); alpha half-life 25.2 +/- 11.3 min; beta half-life 366 +/- 295 min; steady-state volume of distribution 0.74 +/- 0.75 l/kg; volume during elimination phase 1.53 +/- 1.27 l/kg; total body clearance 3.2 +/- 1.7 ml/min./kg. Accordingly, with respect to the pharmacokinetics of indomethacin, children seem to mature early, not later than at the age of one year.     

Clinical pharmacokinetics of dothiepin. Single-dose kinetics in patients and prediction of steady-state concentrations

The pharmacokinetics of dothiepin were evaluated in 9 depressed patients following a single oral dose of 75 mg. Blood and plasma concentrations of dothiepin and 2 major metabolites, northiaden and dothiepin S-oxide, were measured by gas chromatography/mass fragmentography. The mean (+/-SD) peak plasma concentrations of dothiepin were 49 +/- 27 micrograms/L at 3 +/- 1.2h. Mean (+/-SD) estimates of other parameters were as follows: absorption half-life 1.1 +/- 1.1h; distribution half-life 2.2 +/- 0.8 h; elimination half-life 25 +/- 7h; apparent volume of distribution 70 +/- 62 L/kg; and oral clearance 2.1 +/- 1.6 L/kg/h. The mean (+/-SD) peak plasma concentration of dothiepin S-oxide was 125 +/- 43 micrograms/L at 3.5 +/- 1.3h with an elimination half-life of 22 +/- 12 h. The mean peak plasma concentration of northiaden was 6 +/- 3 micrograms/L at 4.5 +/- 1.1h, with an elimination half-life of 31 +/- 12 h. No significant differences were found in pharmacokinetic parameters compared with a previous study in 7 healthy volunteers. When data for the patients and healthy volunteers were combined (n = 16), pharmacokinetic parameters were not found to be affected by age. However, a significant difference was found between males and females for the elimination half-lives of dothiepin and northiaden, and for the apparent volume of distribution of dothiepin. The 24-hour blood/plasma concentrations of dothiepin and dothiepin S-oxide accurately predicted the steady-state concentrations obtained following 4 weeks' treatment with dothiepin 150 mg nocte.     

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.     

The disposition of alfentanil in neonates with respiratory distress

The disposition of continuous infusion alfentanil was evaluated in 13 mechanically ventilated neonates (gestational age 37.6 +/- 2.4 wks) with hyaline membrane disease (n = 7) or persistent pulmonary hypertension of the newborn (n = 6). Alfentanil was administered as a loading dose 8 micrograms/kg, followed by a variable-rate continuous infusion (maximum 10 micrograms/kg/hr; minimum 2.5 micrograms/kg/hr) for 27 hours. Serial plasma samples were obtained for pharmacokinetic analysis. Noncompartmental pharmacokinetic analysis of the data revealed the following estimates (mean +/- SD): total-body clearance 3.24 +/- 2.23 ml/kg/minute, volume of distribution 0.54 +/- 0.21 L/kg, and elimination half-life 4.14 +/- 2.58 hours. A significant effect of alfentanil plasma concentration on total-body clearance was found (r = -0.75; p = 0.02), suggesting nonlinear pharmacokinetics. No correlation was seen between total-body clearance and alfentanil dose (r = -0.37; p = 0.32). The results suggest that a larger dose-proportionality study is required to determine the linearity or nonlinearity of alfentanil pharmacokinetics in neonates.     

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 valproic acid in patients with bipolar disorder

The pharmacokinetics of valproic acid (VPA) were studied in nine patients with bipolar disorder who were receiving VPA as prophylactic therapy, following the full daily dose (400-1500 mg), on which the patients had been maintained for at least the past 3 months. The data from our study showed that the pharmacokinetics of valproate followed a two compartment open model. A time lag of 1-2 h was observed in each patient, followed by rapid absorption, with the peak concentrations being recorded approximately 4 h after drug administration. The average 12 h trough concentration was found to be 54.73+/-11.96 microg/ml. The plasma level decline was biphasic with a terminal half-life of 14.2+/-6.39 h. Total plasma clearance was 0.095+/-0.035 ml/min/kg. The steady-state apparent volume of distribution was found to be 0.11+/-0.05 l/kg. A positive correlation (r = 0.69) was found between the dose (mg/kg) and steady-state serum concentration (Css) of VPA and all patients, except one, had their Css above 50 microg/ml. Most of the pharmacokinetic parameters in this study involving euthymic bipolar patients on long-term VPA monotherapy were found to be in agreement with those reported in literature on seizure disorder patients on similar regime; however, the plasma elimination half-life appears to be prolonged in bipolar patients.     

Pharmacokinetics of intravenously administered haem arginate.

The pharmacokinetics of haem were investigated after intravenous administration of a therapeutic dose of haem arginate (3 mg haem kg-1) to four healthy volunteers and four symptomless porphyric patients. Plasma haem concentrations were measured also during a treatment course of four infusions in six patients with porphyria. Plasma haem concentrations declined monoexponentially over 48 h in both healthy volunteers and porphyric patients, with a mean +/- s.e. mean elimination half-life of 10.8 +/- 0.6 h. Other kinetic parameters were also similar in the two groups, total plasma clearance was 3.7 +/- 0.4 ml min-1 and volume of distribution was 3.37 +/- 0.34 l. In the multiple dose study the elimination half-life increased significantly, from 11.3 +/- 0.4 h to 18.1 +/- 1.4 h over 4 consecutive days. Plasma haemopexin values decreased with time after a single haem arginate dose. The infusion of haem arginate did not cause thrombophlebitis.     

Pharmacokinetics of atenolol in patients with terminal renal failure and influence of haemodialysis.

1 The pharmacokinetics of atenolol, after 200 mg orally, were studied in 18 patients with terminal renal insufficiency (creatinine clearance less than 5 ml/min), of whom twelve were being treated by chronic dialysis. 2 The peak plasma level, 1.59 +/- 0.43 mg/l, was reached in 4.7 +/- 2.1 h. 3 Without dialysis treatment, the apparent plasma half-life of atenolol was greatly increased (73.4 +/- 28.8 /). During dialysis, it dropped to 7.5 +/- 3.7 h but returned to 51.2 +/- 17.3 h after dialysis. The plasma atenolol plot was a rising slope for a few hours after the end of dialysis. 4 Renal clearance of atenolol was very low (4.6 +/- 1.5 ml/min). 5 Plasma clearance during dialysis was 42.6 +/- 21.3 ml/min for a mean blood flow-rate of 236 +/- 25 ml/min through a cuprophane membrane dialyser. 6 These results suggest that dosage should be modified for these patients.     

Pharmacokinetic studies of [14C]-flumecinol in humans

The pharmacokinetics of 14C-labelled 3-trifluoro-methyl-alpha-ethylbenzhydrol (flumecinol, RGH-3332, Zixoryn), a hepatic enzyme inducer, has been studied in 6 male healthy volunteers after a single oral dose of 100 mg (11.1 Mbq; 300 microCi). Flumecinol concentration in plasma was determined (0-96 h) by capillary gas-liquid chromatography. Total radioactivity was assayed by liquid scintillation counting. The peak concentration of unchanged flumecinol in the plasma (130.2 +/- 37.7 ng/ml S.D.) was detected 2.1 h after dosing. The maximum total radioactivity concentration (1414.4 +/- 158.9 ng eq./ml) was found at 2.3 h. The ratio of the plasma radioactivity level to unchanged flumecinol indicated a rapid metabolic transformation and a marked first-pass effect in man. A two-compartment open model was constructed to describe the pharmacokinetics of the drug. The unchanged drug was eliminated from plasma with a biological half-life of 20.7 +/- 1.8 h giving a total body clearance value of 100.9 +/- 33.8 l/h. The volume of distribution of flumecinol was found to be 41.4 +/- 18.4 l/kg. However, the biological half-life of total radioactivity was much longer (35.2 +/- 11.9 h) than that of the decrease of unchanged drug. The value of total body clearance (4.1 +/- 0.6 l/h) and volume of distribution (3.2 +/- 1.6 l/kg) were found to be much lower than that of unchanged flumecinol. Radioactivity excreted with urine was 78.8 +/- 5.9% and with faeces 12.0 +/- 5.3% during 120 h.     

Characterization of the pharmacokinetics of bisantrene (NSC-337766)

The pharmacokinetics of bisantrene, 9,10-anthracenedicarboxaldehyde bis [4,5-dihydro-1 H-imidazol-2-yl) hydrazone) dihydrochloride were evaluated during a Phase I clinical investigation. Bisantrene at doses of 20 to 280 mg/m2 was administered by variable infusion rates to nine patients with advanced metastatic cancer. Bisantrene's plasma clearance followed a triexponential pattern with a harmonic mean terminal half-life (t1/2 gamma) of 26 h. The steady state volume of distribution (Vdss) was large, averaging 627 l/m2. Plasma clearance averaged 42.6 +/- 6.7 l/h/m2. The cumulative urinary excretion of bisantrene was 3.6 +/- 1.6% at 48 h.     

Pharmacokinetics and efficacy of pirmenol hydrochloride in the treatment of ventricular dysrhythmia

Pirmenol hydrochloride (CI-845), a new antiarrhythmic agent available for both oral and intravenous administration, was given to seven patients with chronic ventricular dysrhythmia in an open-label fashion. After intravenous infusion of 150 mg over 30 min, the mean (+/- SD) peak plasma concentration achieved was 2.14 +/- 0.75 microgram/ml. The terminal elimination half-life, the volume of the central compartment, and the total body clearance averaged 6.5 h, 0.70 +/- 0.36 L/kg, and 3.0 +/- 2.6 ml/min/kg, respectively. After a single 150-mg oral dose, the peak plasma concentration of 1.3 +/- 0.55 microgram/ml was achieved 1 to 3 h after dosing. The mean apparent elimination half-life was 7.6 h. An estimated absorption lag time ranging from 14 to 37 min was observed in all but one patient. The mean absolute bioavailability for the oral dose was 87%. Dysrhythmia data were available in six patients. Complete (100%) suppression of ventricular ectopic beats occurred in four patients for 1/2 to 15 h after intravenous infusion, and in three patients for 7 to 25 h after oral dose. This suppression occurred with a plasma pirmenol level as low as 0.4 microgram/ml. No significant side effects were observed.     

Pharmacokinetics of vinpocetine and its metabolite, apovincaminic acid, in plasma and cerebrospinal fluid after intravenous infusion

The pharmacokinetics of vinpocetine (ethyl apovincaminate, Cavinton) and its metabolite, apovincaminic acid, was studied in patients with cerebrovascular disorders. Vinpocetine (1 mg/kg) was infused intravenously over 25 min. The elimination half-life of the parent drug in plasma was 4.7+/-2.13 h. Total clearance of vinpocetine was 0.79+/-0.1 1 h(-1) kg(-1). The presence of vinpocetine in cerebrospinal fluid shows that the drug is able to pass through the blood-brain barrier and reach the central nervous system which is a possible site of action. The maximum increase of cerebral blood flow (25%) was measured at 32 min after the start of the infusion.     

Pharmacokinetics and hemodynamic effects of long-term nifedipine treatment in hypertensive patients

In six patients with essential hypertension, pharmacokinetics and pharmacodynamics of nifedipine were investigated during 6 weeks of treatment. On day 1 nifedipine was infused intravenously (6.0 mg within 60 min), and on day 2 oral nifedipine treatment (20-mg tablets, twice daily) was started. Patients came to the hospital once weekly, when blood samples were taken and blood pressure and heart rate were assessed prior to tablet intake and 3 h later. After 6 weeks of oral treatment the intravenous infusion experiment was repeated. At the first intravenous nifedipine infusion a total systemic plasma clearance of 671 +/- 240 ml/min (mean +/- SD), an elimination half-life of 95 +/- 36 min, and a volume of distribution of 60.2 +/- 11.9 L were found. Protein unbound fraction of nifedipine amounted to 4.6 +/- 0.3%. After 6 weeks of oral treatment half-life was almost doubled (p less than 0.05), whereas in most patients the volume of distribution had slightly increased and systemic plasma clearance was decreased. Using a sigmoidal model, hemodynamic effects were fitted to nifedipine plasma concentrations. After 6 weeks the maximal effect of intravenous nifedipine on both systolic and diastolic blood pressures had significantly decreased. In four patients the potency had decreased considerably. During oral nifedipine treatment the mean plasma half-life was 5.8 +/- 1.0 h; trough concentration was 11.3 +/- 4.1 ng/ml and peak concentrations were 36.8 +/- 14.3 ng/ml. During chronic treatment heart rate was not significantly changed, whereas systolic and diastolic blood pressures were significantly reduced (p less than 0.02 and less than 0.01, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)     

Plasma pharmacokinetics of cinmetacin following oral administration in healthy volunteers

The pharmacokinetics of a single 600 mg oral dose of 1-cinnamoyl-2-methyl-5-methoxy-3-indolylacetic acid (cinmetacin, Cindomet) was studied in 8 healthy volunteers of both sexes. Plasma levels of the drug were assayed by using an HPLC technique ad hoc devised. Following administration, the Cmax was reached at the 2nd h in 7 out of 8 subjects with an average value of 18.19 micrograms/ml; 12 h after the dose (last sampling time) appreciable plasma levels of cinmetacin were measured, corresponding to 17.2% of the maximum average concentration. The mean values +/- S.E. concerning the elimination half-life, the total volume of distribution, the total plasma clearance and the total area under the curve were 3.80 +/- 0.21 h, 0.28 +/- 0.03 l/kg, 0.051 +/- 0.005 l/kg/h, and 125.64 +/- 15.97 micrograms.h/ml, respectively. The plasma decay of cinmetacin was monophasic and the data were interpreted according to a one-compartment open model. Overall results indicate that cinmetacin is well and rapidly absorbed orally and widely distributed in body fluids.     

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).     

The pharmacokinetics of high dose metoclopramide in patients with neoplastic disease.

High dose metoclopramide infusions (10 mg/kg) were administered to nineteen patients with bronchial carcinoma who were receiving intravenous cyclophosphamide as single agent chemotherapy. Considerable interindividual variability in metoclopramide disposition was observed. Mean clearance was 0.33 +/- 0.13 (s.d.) l h-1 kg-1, mean volume of distribution at steady state was 3.8 +/- 1.2 (s.d.) l/kg and mean elimination half-life was 8.3 +/- 4.4 (s.d.) h. These results were significantly different from mean values previously reported for young healthy volunteers given conventional doses (0.70 l h-1 kg-1, 2.2 l/kg and 2.6 h respectively). Significant correlations were found between serum urea, serum creatinine and metoclopramide clearance. The metoclopramide regimens were well tolerated and, with the exception of two patients, were completely effective in the prevention of nausea and vomiting. To achieve and maintain target serum metoclopramide concentrations of 1 microgram/ml, we now administer a loading infusion of 3.61 mg/kg over 30 min followed by a maintenance infusion of 0.36 mg kg-1 h-1 for 10 h. Cyclophosphamide is normally administered concurrently with the second infusion. For patients with evidence of mild renal impairment, the maintenance infusion rate of metoclopramide hydrochloride should be adjusted according to the predicted individual clearance value; CL (l h-1 kg-1) = 0.57 - [0.036 X urea (mmol/l)].     

The pharmacokinetics of alfentanil in gynecologic surgical patients

The pharmacokinetics and serum protein binding of alfentanil during continuous intravenous infusion were determined in 11 women who were either healthy (American Society of Anesthesiologists [ASA] physical status 1) or had mild systemic disease (ASA physical status 2). Anesthesia was induced with intravenous thiopental 2 mg/kg and alfentanil 50 micrograms/kg and maintained with constant intravenous alfentanil infusions of 1-3 micrograms/kg/min until approximately ten minutes before the end of surgery. Venous blood samples were obtained after the bolus of alfentanil was administered and at various times during and after the alfentanil infusion. Serum alfentanil concentrations were measured by gas-liquid chromatography. There was considerable interpatient variability in alfentanil pharmacokinetics and serum protein binding. The mean +/- SD alfentanil serum clearance, volume of distribution at steady state (Vss), and elimination half-life were 5.2 +/- 2.0 mL/min/kg, 0.47 +/- 0.1 L/kg, and 97 +/- 52 minutes, respectively. The mean fraction of alfentanil unbound in serum (fu) was 0.18 +/- 0.08. There was a time-dependent decrease in alfentanil serum clearance that correlated with increasing duration of surgery. This decrease in clearance resulted in a prolonged alfentanil half-life. These results indicate there is considerable interpatient variability in the pharmacokinetic parameters and serum protein binding of alfentanil in these patients and suggest that the infusion rate of alfentanil during maintenance anesthesia should be adjusted for individual patient response. Infusion rates may need to be tapered during prolonged operations.     

Pentachlorophenol toxicokinetics after intravenous and oral administration to rat.

1. The toxicokinetics of pentachlorophenol (PCP) were studied in rats. Doses of 2.5 mg/kg were given i.v. (bolus, five rats) and orally (gastric intubation, five rats). Concentrations in plasma, urine and faeces were measured by capillary g.l.c. with electron-capture detection. 2. After i.v. administration, the clearance and volume of distribution at steady state were 0.026 +/- 0.003 l/h per kg and 0.25 +/- 0.02 l/kg, respectively. These two parameters exhibit low inter-rat variability (coefficients of variation less than 15%). The half-life of the initial decline of PCP plasma concn. was less than 1.3 h, while the second phase half-life was 7.11 +/- 0.87 h. 3. After oral administration the peak plasma concn. (7.3 +/- 2.8 micrograms/ml) occurred between 1.5 and 2 h and absorption was complete (bioavailability = 0.91-0.97). No distinct distribution phase was observed and the elimination half-life was 7.54 +/- 0.44 h. 4. PCP clearance is essentially metabolic since only 5.3 +/- 0.2% dose is eliminated unchanged by the kidney. About 60% dose was recovered in urine, mainly as conjugated PCP and conjugated tetrachlorohydroquinone (TCHQ). 5. For both routes of administration, about 10% dose was recovered in faeces as PCP and/or metabolites, which indicates that biliary excretion contributes to total elimination.