Disposition kinetics of dibekacin in normal subjects and in patients with renal failure.
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Dibekacin pharmacokinetics was studied in ten healthy volunteers and six patients with renal failure presenting Clcr less than 10 ml X min-1 per 1.73 m2 of body surface, given as a slow intravenous bolus to the volunteers and as a 30-minute intravenous infusion to the patients. The antibiotic was assayed in plasma and urine by means of a microbiological method using Bacillus subtilis. A two-compartment kinetic model was used to describe the bi-phasic decline of the plasma concentration thus establishing the different pharmacokinetic parameters. Elimination parameters beta, k10 and total body clearance were markedly diminished in renal patients (p less than 0.001): t1/2 beta was 2.0 h, k10 = 0.016 min-1 and Cl = 0.87 ml X min-1 kg body weight in normal subjects and t1/2 beta = 21.4 h, k10 = 0.0011 min-1 and Cl = 0.131 ml X min-1 per kg in the patients. Other kinetic parameters, as distribution (alpha) and transfer (k12, k21) constants were lower in patients than in volunteers. Also the different terms of volume of distribution of the two-compartment model (V1, Vdss, Vdarea) were significantly higher in patients than in normal subjects (p less than 0.05). A good correlation (r = 0.987) between patients' beta constant and creatinine clearance was found. A similar relationship between serum creatinine levels and disposition half-life was found (r = 0.955). Urinary recovery at 24 h was 89.0% of the dose given to normals and 15.8% of the dose given to patients.Keywords:
Intravenous bolus
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Bolus (digestion)
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Lomefloxacin pharmacokinetics were investigated in 6 normal subjects and 24 uremic patients after a single oral dose of 400 mg. In subjects with normal renal function, the peak level in plasma averaged 3.5 +/- 0.9 micrograms/ml (mean +/- standard deviation) and was obtained at 1.3 +/- 0.9 h. The absorption rate constant was 3.8 +/- 1.6 h-1. The terminal half-life was 7.77 +/- 0.95 h. The apparent volume of distribution was 2.54 +/- 0.66 liters/kg. Total body and renal clearances were 259 +/- 83 and 200 +/- 55 ml/min per 1.73 m2, respectively. The percentage of the dose recovered unchanged in 48-h urine was 80.6 +/- 2.8. In uremic patients, the terminal half-life increased in relation to the degree of renal failure: from 8 h in normal subjects to 38 h in severely uremic patients (glomerular filtration rate, less than 10 ml/min). Renal insufficiency did not significantly modify the peak level in plasma, the time to peak, the apparent volume of distribution, or the nonrenal clearance of lomefloxacin. The dialysis clearance of lomefloxacin was 54 +/- 13 ml/min. Linear relationships were found between lomefloxacin pharmacokinetic parameters and glomerular filtration rate data. Dosage adjustments are necessary in uremic patients.
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Seven healthy adult male Wistar rats,with an average weight of 250 g,were used to study the pharmacokinetics characteristics of doxycycline in plasma and urine after intravenous administration at10mg/kg.The doxycycline concentrations in plasma and urine samples were determind by a high performance liquid chromatography method.Then the plasma concentrations versus time data were subjected to compartmental analysis to obtain its pharmacokinetics parameters in plasma,while rate method was used to calculate the pharmacokinetics parameters in urine.The disposition of doxycycline after single intravenous injection was best described by a two-compartment open model.And the main plasma pharmacokinetics parameters were as flows:the volume of distribution(Vd)was(1493.48±243.65)mL/kg,distribution rate constant(α)was(13.70±5.92)h-1,elimination rate constant(β)was(0.15±0.03)h-1,and body clearence(Cl)was(216.06±52.98)mL/h/kg.The pharmacokinetics parameters of doxcycline derived from rate method were listed below:βwas(0.13±0.02)h-1,renal excretion rate constant(ke)was(0.08±0.02)h-1,renal clearence(Clre)was(113.35±18.02)mL/h/kg,and hepatic clearence(Clhe)was(102.71±32.14)mL/h/kg.In conclusion,doxycycline was distributed extensively and eliminated slowly in rats after intravenous administration.Liver and kidney shared the same abilities for elimination of doxcycline from rats.
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The pharmacokinetics of ciprofloxacin were evaluated after single iv bolus injections of 50, 100 and 250 mg in eight young, healthy male volunteers. Concentrations were determined by high-performance liquid chromatography. The mean terminal half-life was 3.33, 3.73 and 3.45 h for 50, 100 and 250 mg doses, respectively. No significant differences between the three dose levels were noted for terminal half-life, total and renal clearances, distribution volume (Vd(ss)) and percentage of dose recovered in urine over 24 h. The areas under the serum concentration curves were proportional to the given dose. We conclude that distribution and elimination of ciprofloxacin is not dose dependent.
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Pharmacokinetics and distribution of enrofloxacin in plasma, milk and urine were studied after a single intravenous dose of 5 mg/kg in six healthy goats. Therapeutic concentration of ≥0.12 μg/ml was maintained up to 10, 30 and > 48 hr in plasma, milk and urine, respectively. The drug showed a distribution half life (t½ α) of 0.60±0.10 hr and elimination half life (t½ β) of 2.82±0.33 hr. A value of 1.11±0.22 for tissue to plasma concentration ratio (T ≈ P) and large volume of distribution (Vdarea) of 2.34±0.54 L/kg indicated that the drug is distributed well in different body tissues and fluids. A total body clearance value (Cls) of 9.40±1.36 ml/kg/min was observed.
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We have previously shown with i.v. bolus studies that the elimination of propofol is much slower than previously reported. Now we have studied the implications of this for prolonged i.v. infusion of propofol in seven patients who received continuous infusions of propofol for up to 9 h. Values of elimination half‐life ranged from 13.1 to 44.7 h, systemic clearance from 1.02 to 1.63 l h‐1 and volume of distribution from 1390 to 3940 l and these were similar to those obtained with bolus administration. The large volume of distribution is consistent with the high octanol/blood partition coefficient, which was found to be 72.0. Despite the very long elimination half‐life, blood propofol concentrations appeared to approach steady state within 20 min rather than the 4‐5 half‐lives normally expected. This is because for this drug, which displays multicompartment pharmacokinetics, the rate of initial rise of blood concentrations is governed primarily by the very short distribution half‐life of the drug. Therefore, the long elimination half‐life of propofol is probably of little significance in designing infusions regimens, but the lower systemic clearance should be taken into account to avoid unwanted accumulation.
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Fifteen children (mean age±SD: 6.4±3.4, range: 2–12 years) with an acute asthma attack were treated by an intravenous dosage regimen of theophylline (30 min loading infusion of 6 mg/kg body weight followed by a constant infusion of 1 mg/kg, twice for 6 hr each). Three blood samples were drawn (each 15 min after the bolus infusion and after the two infusion periods of 6 hr). Plasma clearance (CL), apparent volume of distribution (Vd) and elimination half-life (t1/2) were estimated by the Bayesian approach using either only the first peak level (Bay 1) or all three monitored concentrations (Bay 3). These values were compared to the parameters calculated by a standard pharmacokinetic procedure (SC). Therapeutic steady state plasma levels around 12 μg/ml were rapidly achieved, and the pharmacokinetic parameters (CL=1.1–1.5 ml/min/kg, Vd=0.44 - 0.501/kg, t1/2 = 3.5–5.4 hr) differed slightly between the 3 methods applied. There was a significant linear correlation between the Bayesian-derived and SC-derived pharmacokinetic parameters. However the method Bay 1 seems to overestimate the elimination rate of theophylline more than Bay 3 does. In conclusion, Bayesian-based therapeutic plasma level monitoring (Bay 3 are better than Bay 1) can be utilized for individualized pharmacokinetic calculations and proper dosage predictions of theophylline in pediatric patients.
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Human physiology
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Cisplatin was administered to seven patients with advanced cancer in divided doses of 40 mg/m2 body surface daily for 5 consecutive days. The pharmacokinetics of total Pt was studied on the days 1, 3 and 5 of infusion. The renal function was assessed through the parameters usually applied in the clinical practice (serum creatinine level, creatinine clearance, urinary volume). Pt pharmacokinetics and the renal function did not show modifications outside the normal range. However, on day 5 of treatment patients showed increased alpha-half life and AUC of plasma Pt, as well as decreased Pt total body clearance and Pt renal clearance, associated to a significant (although still within normal range) increase in serum creatinine and a decrease in urinary volume. Moreover, a correlation between Pt pharmacokinetics and renal parameters (measured as the difference between the values of days 1 and 5 of treatment) was also found: the increase in creatinine was directly related to a decrease in Pt renal clearance and inversely related to Pt peak level in urine, while the latter was inversely related to a reduction of Pt renal clearance. It was concluded that very high doses of cisplatin are well tolerated in patients, although some parameters might suggest early impairment of the renal function.
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