Distribution and elimination kinetics of carbamazepine in man

Summary Carbamazepine (2.7–3 mg/kg) was administered orally as an alcoholic solution (50% v/v) to eight healthy volunteers. Two of the subjects were also given 50 mg and 100 mg of carbamazepine in alcoholic solution and 200 mg as a tablet. Plasma concentrations, which were analysed by mass fragmentography, reached a maximum 1 – 7 hours after dosing, and then declined monoexponentially with half-lives ranging from 24 to 46 hours. The half-lives were independent of dose. The apparent distribution volume ranged from 0.79 to 1.40 l/kg. It was found that 72% of carbamazepine was bound to plasma proteins with little interindividual variation, and this was not influenced by the presence of diphenylhydantoin or phenobarbital in therapeutic concentrations. The pharmacokinetic parameters calculated from single oral doses were used to predict the steady-state plasma concentration expected after treatment with multiple doses of 200 mg three times daily. The predicted steady-state concentration was 2 – 3 times higher than that reported in patients undergoing chronic treatment with carbamazepine at this dose level, i.e. the pharmacokinetics of carbamazepine apparently change during multiple dosing.Dedicated to the memory of Balzar Alexandersson, MD.Medical Research Council (U.K.) Travelling Fellow     

Pharmacokinetics of intravenously administered bumetanide in man

Disposition of [ ¹⁴C] bumetanide administered intravenously to four healthy volunteers could be described by a triexponential equation. The mean half-lives associated with each exponent were 5.9 min, 46 min, and 3.1 hr, respectively. The largest fraction of dose was eliminated during the second phase; only 17% was eliminated during the last phase. The total plasma clearance averaged 228 ml/min, with renal clearance about one-half of this value. The recovery of unchanged bumetanide in urine over 2 days was 47% of the dose, while the total recovery of radioactivity in urine averaged 82% of dose. In plasma 93% of bumetanide was bound to proteins. Thus bumetanide is rapidly eliminated by both renal and nonrenal mechanisms. The elimination kinetics resembled those described for furosemide.     

Pharmacokinetics of intravenously administered L-5-hydroxytryptophan in man.

The pharmacokinetics of 5-hydroxytryptophan were investigated in relation to intravenous administration of single doses of the amino acids (0.2 mg/kg b.wt.) to five patients pretreated for one week with carbidopa, an L-aromatic amino acid decarboxylase inhibitor. The plasma concentration/time lapse of 5-hydroxytryptophan exhibited bi-exponential disposition characteristics and the data obtained could be closely fitted to an open two compartment pharmacokinetic model with elimination taking place from the central compartment. The apparent composite 1. order rate constants alpha and beta were 1.433 hr-1 +/- 0.177 S.D. and 0.113 hr-1 +/- 0.012 hr-1 S.D., respectively. The biological half-life of 5-hydroxytryptophan under the experimental conditions was thus about 6 hours. The apparent volume of the central compartment, Vc, was found to be 0.336 1 kg-1 +/- 0.059 S.D. and the plasma clearance 0.105 1 hr-1 kg-1 +/- 0.015 S.D. The derived pharmacokinetic constants were used for doses regimen calculations and predetermination of the plasma concentration/time lapse, during continuous intravenous infusion therapy. Measured plasma concentrations of 5-hydroxytryptophan during infusion deviated by less than 10 per cent from the predicted values. However, the infusions had to be stopped in four of the experiments because the patients became nauseated and vomited after total doses of only 36--128 mg.     

The kinetics of salivary elimination of cyclophosphamide in man.

1 The concentrations of cyclophosphamide in plasma and saliva were determined in seven patients following administration of single doses of cyclophosphamide during chemotherapy for lymphoma. 2 The saliva/plasma ratio was 0.77 +/- 0.24 (s.d.) and showed no time-dependence being rapidly established following intravenous and oral administration. 3 The T 1/2 of cyclophosphamide (8.38 +/- 2.25 h) determined from salivary measurements was not significantly different from that in plasma (8.24 +/- 2.60 h). It was not possible to estimate the apparent volume of distribution or total body clearance utilizing the salivary cyclophosphamide concentration without appropriate correction for the saliva/plasma concentration ratio. 4 The binding to the plasma protein of normal plasma of cyclophosphamide was 13.4 +/- 5.3%. The Scatchard plot for binding to bovine serum albumin indicates only weak binding to non-specific sites. 5 Salivary cyclophosphamide therefore indicates the concentration of the unbound fraction of plasma cyclophosphamide.     

Distribution and elimination of hydroflumethiazide in man

Summary The pharmacokinetics of hydroflumethiazide (HFT) were investigated after intravenous and oral administration to healthy subjects. After intravenous infusion, HFT behaved according to a three-compartment model. Two distribution phases were observed, with mean half-lives of 0.26 and 0.85 h, reflecting distribution to red blood cells and tissues. Mean biological half-life (t_1/2β ) after infusion was 5.2 h. Renal blood and plasma clearance of HFT, as well as the ratio renal blood clearance/renal plasma clearance of HFT, were lower after infusion than during the infusion, due to the distribution characteristics of HFT. After a single oral dose of 2 μmol/kg, t_1/2β was significantly shorter in all subjects than after a single oral dose of 6 μmol/kg, with mean t_1/2β of 8.7 and 17.9 h, respectively. Due to lack of a sufficiently sensitive method for determination of HFT in plasma, it could not be established whether the observed dose-dependent difference in biological half-life of HFT was caused by variation in renal clearance and/or the volume of distribution.     

Plasma kinetics and urinary elimination of saccharin in man

The plasma kinetics and urinary elimination of saccharin were studied in 3 groups each of 5 healthy male volunteers given the sweetener as three different single oral doses (50, 150 and 333 $\text{mg}\text{60 kg}$ body weight). Saccharin concentrations were determined by gas liquid chromatography-stable isotope dilution mass fragmentography.The compound was rapidly absorbed through the gastrointestinal tract, reaching plasma peak concentrations between 30 and 60 min after intake. Plasma saccharin elimination was also fast, with a monoexponential pattern of decay. At the 3 doses studied saccharin was excreted in urine within a few hours, about 60% of the dose being excreted unchanged at 6 h and 76% at 24 h.     

Passage of intravenously administered tubocurarine into the liquor space in man and dog

1. In anaesthetized patients under controlled respiration, samples of lumbar cerebrospinal fluid were withdrawn 15 and 60 min after an intravenous injection of 30 mg tubocurarine. When tested on the frog rectus muscle preparation contracted by acetylcholine, they exerted curare-like activity which corresponded to between 0.05 and 0.33 mug/ml tubocurarine.2. In dogs anaesthetized with pentobarbitone sodium and artificially ventilated, two procedures were adopted to find out if tubocurarine passes into the liquor space after an intravenous injection of 0.3 or 3 mg/kg and during its intravenous infusion at a rate of 10 (mug/kg)/minute. Either samples of cisternal cerebrospinal fluid (c.s.f.) were collected, or different regions of the liquor space were perfused with artificial c.s.f. and the effluent was collected. The samples of c.s.f. and the effluent were assayed for curare-like activity on the frog rectus muscle.3. After the intravenous injection of tubocurarine samples of cisternal effluent collected during perfusion from lateral ventricle to cisterna exerted curare-like activity. It corresponded to 20 ng/min tubocurarine in the sample collected during the first 15 min after the injection of 0.3 mg/kg and to 40-60 ng/min in the samples collected up to 2 h after the injection of 3 mg/kg.4. During intravenous infusion of tubocurarine the cisternal c.s.f. as well as the effluent from the perfused regions of the liquor space exhibited curare-like activity. Expressed in equivalents of tubocurarine, the activity in the cisternal c.s.f. ranged from between 0.1 and 0.75 mug/ml. On perfusion from lateral ventricle to aqueduct or cisterna, the activity ranged from between 3 and 25 ng/min in the aqueductal and from between 4 and 40 ng/min in the cisternal effluent. On perfusion from the lumbar-spinal subarachnoid space to cisterna it ranged from between 6 and 55 ng/min in the cisternal effluent.     

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.     

Relationship between renal function and elimination kinetics of pindolol in man

Summary In view of a previous report suggesting an increased metabolism of the beta-blocking agent pindolol with decreasing renal function in man, the relationship between renal function and the elimination kinetics of pindolol has been re-examined. There is a statistically significant positive correlation between the renal clearances of pindolol and creatinine but there is no correlation between the non-renal clearance of pindolol and the renal clearance of creatinine. Thus, there is no evidence of an increased metabolism (non-renal clearance) of pindolol with decreasing renal function.     

Effect of chronically administered ketoconazole on the elimination of theophylline in man

Ketoconazole, a nitrogen-substituted imidazole, has been shown to be a potent in vitro inhibitor of cytochrome P-450-mediated metabolic processes. Conflicting reports exist concerning the in vivo effect of ketoconazole on concomitantly administered drugs that require these metabolic processes for clearance. Therefore, the effect of multiple-dose ketoconazole on the elimination of theophylline, a drug metabolized by cytochrome P-450, in ten healthy, nonsmoking males (aged 18-40 years) was evaluated. Each subject received aminophylline 6 mg/kg iv before and at the end of seven days of ketoconazole 200 mg/d po. Theophylline serum concentrations were determined by fluorescence polarization immunoassay (TDx) at 12 time points over the 24-hour period following each infusion. No statistical difference (two-tailed t-test) in half-life (mean +/- SD 7.8 +/- 1.8 vs. 8.2 +/- 1.9 h) or clearance (0.797 +/- 0.201 vs. 0.722 +/- 0.133 ml/min/kg) could be demonstrated for theophylline before or after ketoconazole administration. Theophylline dosage adjustment is probably not necessary for concomitant theophylline and ketoconazole drug therapy.     

Human kinetics of orally and intravenously administered low-dose 1,2-(13)C-dichloroacetate

Dichloroacetate (DCA) is a putative environmental hazard, owing to its ubiquitous presence in the biosphere and its association with animal and human toxicity. We sought to determine the kinetics of environmentally relevant concentrations of 1,2-(13)C-DCA administered to healthy adults. Subjects received an oral or intravenous dose of 2.5 microg/kg of 1,2-(13)C-DCA. Plasma and urine concentrations of 1,2-(13)C-DCA were measured by a modified gas chromatography-tandem mass spectrometry method. 1,2-(13)C-DCA kinetics was determined by modeling using WinNonlin 4.1 software. Plasma concentrations of 1,2-(13)C-DCA peaked 10 minutes and 30 minutes after intravenous or oral administration, respectively. Plasma kinetic parameters varied as a function of dose and duration. Very little unchanged 1,2-(13)C-DCA was excreted in urine. Trace amounts of DCA alter its own kinetics after short-term exposure. These findings have important implications for interpreting the impact of this xenobiotic on human health.     

Population kinetics of tobramycin in neonates

The population kinetics of tobramycin were studied in 140 neonates (100/40 patients for the index/validation groups, respectively) of 30 to 42 weeks' gestational age and 0.8 to 4.25 kg current body weight in their first 2 weeks of life, undergoing routine therapeutic drug monitoring of their tobramycin serum levels. The 365 tobramycin concentration measurements obtained were analyzed by use of NONMEM according to a one-compartment open model with zero-order absorption and first-order elimination. The effect of a variety of demographic, developmental, and clinical factors (gender, height, birth weight, current weight, gestational age, postnatal age, postconceptional age, and serum creatinine concentration) on clearance and volume of distribution was investigated. Forward selection and backward elimination regression identified significant covariates. The final pharmacostatistical model with influential covariates was as follows (full population): clearance (L/h) = 0.0508 x current weight (kg), multiplied by 0.843 if birth weight was 2.5 kg or less (low-birthweight infants), and volume of distribution (L) = 0.533 x current weight (kg). Using the proportional error model for the random-effects parameters, interindividual variability for clearance and for volume of distribution was determined to be 25.8% and 21.9%, respectively, and the residual variability was 19.2%. In this study, the use of the NONMEM gave significant and consistent information on the pharmacokinetics and the determinants of the pharmacokinetic variability of tobramycin in neonates when compared with available bibliographic information. Moreover, the final population pharmacokinetic model may be used to design a priori recommendations for tobramycin and to improve the dosing readjustments through Bayesian estimation.     

Muscle-relaxant effects of intravenously administered micronomicin

Pharmacological effects, mainly on its muscle-relaxant of micronomicin (MCR) were studied. Intravenous infusion of MCR at a dose of 20 mg/kg/hour did not influence on both respiration rate and cardiovascular functions in anesthetized rabbits. When MCR was injected to anesthetized rabbit at an intravenous dose of 100 mg/kg, a respiratory arrest followed by a cardiac arrest was observed. This effect was antagonized by either treatment with CaCl2 or artificial respiration. In slant test, MCR at a dose of 100 mg/kg (i.v.) in mice induced muscle relaxation. This effect was weakened by slowing the injection speed of the drug. Intravenous injection of MCR potentiated the lethality induced by either d-tubocurarine or succinylcholine. Intravenous injection of MCR influenced on neither pentobarbital sodium-, ethyl ether-, nor halothane-induced anesthesia in mice. From these results, intravenous infusion of MCR at a dose of 20 mg/kg/hour that is considered as 5 approximately 10 times of clinical dose (120 approximately 240 mg/day) did not influence on both respiration and cardiovascular functions.