Pharmacokinetic study on intravenous rifampicin in man
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One gram ceftriaxone was injected at a constant rate in an intravenous infusion over 30 min to eight elderly subjects (mean age, 70.5 yr) and eight young subjects (mean age, 28.9 yr); the latter served as body weight–matched controls. Plasma and urine samples were collected in serial order for 48 hr and assayed for unchanged drug. Selected plasma samples were subjected to protein binding determinations by equilibrium dialysis. Statistical comparison of data for the old and young indicated no significant changes in means of (1) maximum plasma concentration (140 and 133 µg/ml); (2) elimination rate constant (0.078 and 0.093 hr−1) and elimination t½ (8.9 and 7.5 hr); (3) apparent volume of distribution (10.69 and 11.01 l); (4) plasma clearance (833 and 1023 ml/hr); (5) nonrenal clearance (515 and 606 ml/hr); and (6) percent dose excreted unchanged in urine (39.6 and 41.4). There was, however, a significant decrease in the renal clearance (318 and 416 ml/hr) and a significant increase in the plasma free fractions (0.157 and 0.136 at 100 µg/ml and 0.146 and 0.114 at 60 to 70 µg/ml) of ceftriaxone in elderly subjects. The 24% decrease in renal clearance in the elderly subjects corresponded to the 19% decrease in their creatinine clearance. Since the age-related changes in kinetics were relatively small, it is concluded that dosage adjustment is probably not necessary for elderly subjects requiring ceftriaxone. Clinical Pharmacology and Therapeutics (1984) 35, 19–25; doi:10.1038/clpt.1984.3
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Levels of guanazole (GZ) in plasma and packed cells were determined after a single tracer dose of 14 C‐guanazole or during a 5‐day continuous intravenous therapeutic infusion of unlabeled drug to 5 patients with acute myelocytic leukemia (A ML). The levels of unlabeled drug were determined colorimetrically. GZ injected as a tracer dose was rapidly distributed in an apparent volume of 0.61/kg, which is somewhat less than that of total body water, and the drug appeared to be eliminated essentially unchanged by glomerular filtration. The mean apparent volume of distribution increased by about 15% during infusion. An increase of 60% was also noted in the half‐life (t ½ ) values, with a concomitant decrease in the mean value of renal clearance rate by 40%, except in 1 case. The study demonstrates that monitoring levels of guanazole is possible during infusion therapy and indicates that the data could be used to evaluate pharmacokinetic parameters predicting the time‐course of such levels in patients.
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The disposition and elimination of meperidine were compared in drug and alcohol‐free, age‐matched groups of 8 normal volunteers and 10 patients with cirrhosis of the liver, while controlling the urinary pH at 7.0 or more. After a single rapid intravenous injection, 0.8 mg/kg, plasma meperidine concentration declined biexponentially with the fast (α) and slow (ß) phases having half‐lives in the normal group of 0.19 hr and 3.2 hr (mean values), respectively. In the cirrhotics T½α was not changed but T½ß increased to 7.0 hr (p < 0.001), and this was associated with a reduction in the total plasma meperidine clearance from 1,316 ml/min to 664 ml/min (p < 0.002). Analysis of the data by a two‐compartment open model indicated that meperidine was extensively distributed; initial distribution volume (V 1 ) 2 1.54 lIkg and volume of distribution at steady‐state (Vd ss ), 4.17 lIkg in control subjects. Similar volumes of distribution were noted in cirrhotic patients. The overall first‐order elimination rate constant, k 13 , decreased from 0.672 hr‐ 1 in the normal subjects to 0.242 hrs in the cirrhotics (p < 0.001). The plasma binding (64.3%) and the blood/plasma concentration ratio (0.683) of meperidine in control subjects were not altered in cirrhosis. There were no Significant correlations found between T½ß or plasma clearance in the cirrhotics and the usual biochemical hepatic function tests. The metabolite, normeperidine, was not detected in the plasma of either group. It is concluded that the elimination of meperidine is prolonged in cirrhosis, probably due to impairment of drug‐metaboliZing activity in the liver. Accordingly, caution should be exercised when this drug is administered, particularly for long periods, to patients with cirrhosis.
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-1 body weight intravenously to a group of eight healthy rabbits and compared these results to values in same eight rabbits with EEIF. Pharmacokinetic parameters of ofloxacin in normal and febrile rabbits were determined by using two compartment open kinetic model. Peak plasma level (Cmax) and area under the plasma concentration-time curve (AUC0-α) in normal and febrile rabbits did not differ (P>0.05). However, area under first moment of plasma concentration-time curve (AUMC0-α) in febrile rabbits was significantly (P<0.05) higher than that in normal rabbits. Mean values for elimination rate constant (Ke), elimination half life (t1/2β) and apparent volume of distribution (Vd) were significantly (P<0.05) lower in febrile rabbits compared to normal rabbits, while mean residence time (MRT) and total body clearance (Cl) of ofloxacin did not show any significant difference in the normal and febrile rabbits. Clinical significance of the above results can be related to the changes in the volume of distribution and elimination half life that illustrates an altered steady state in febrile condition; hence, the need for an adjustment of dosage regimen in EEIF is required.
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Cisatracurium, one of 10 isomers of atracurium, undergoes pH and temperature-dependent Hofmann elimination in plasma and tissues. The clearance of cisatracurium due to Hofmann elimination and organ elimination was estimated by applying a nontraditional two-compartment pharmacokinetic model with elimination occurring from both compartments to plasma cisatracurium concentration-time data from 31 healthy adult surgical patients with normal renal and hepatic function. The elimination rate constant from the central compartment, intercompartmental rate constants, and the volume of the central compartment were obtained from the model fit. The elimination rate constant from the peripheral compartment could not be independently estimated in vivo and was therefore fixed to the rate of degradation of cisatracurium in human plasma (pH 7.4 and 37 degrees C) and held constant in the model. Total body clearance, Hofmann clearance, organ clearance, and the volume of distribution at steady-state were derived from the model parameter estimates. Renal clearance was calculated from cisatracurium urinary excretion data from 12 of the 31 patients. Clearance values (mean +/- SD) were 5.20 +/- 0.86, 4.00 +/- 1.04, 1.20 +/- 0.71, and 0.85 +/- 0.32 mL [centered dot] min-1 [centered dot] kg-1 for total body clearance, Hofmann clearance, organ clearance, and renal clearance, respectively. Hofmann clearance accounted for 77% of total body clearance. Organ clearance was 23% of total body clearance. Renal clearance, a component of organ clearance, was 16% of total body clearance. The organ-independent nature of the elimination of cisatracurium was characterized by a relationship between steady-state volume of distribution and total body clearance. The half-life is an independent variable and is not dependent on the total body clearance nor the steady-state volume of distribution. Hofmann elimination is the predominant pathway for cisatracurium elimination in humans. (Anesth Analg 1996;83:1065-71)
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The pharmacokinetics of the new anti‐inflammatory agent tolmetin have been studied after its oral administration to normal subjects and to patients with rheumatoid arthritis. Plasma concentration‐time data were fitted to a one‐compartment open model. Following single oral doses, no basic differences in rates of drug absorption and elimination were found between normal subjects and arthritic patients. For the 12 subjects studied, the overall mean elimination rate constant was 0.839 hr ‒1 , corresponding to a plasma half‐life of 0.83 hr. The drug was rapidly absorbed and had a mean apparent volume of distribution of 0.098 1/kg. Plasma levels and pharmacokinetic parameters of tolmetin in arthritic patients after multiple dosing were similar to those after a single dose.
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The pharmacokinetics of 3H-labeled digoxin and metildigoxin were compared in six anuric patients. The following means +/- s.e.m. were obtained: extrarenal clearance of digoxin, 43.3 +/- 5.4 ml/min, of metildigoxin, 30.3 +/- 2.9 ml/min; distribution volume of digoxin, 315 +/- 29 1, of metildigoxin, 258 +/- 22 1; rate constant for elimination of digoxin, 0.0086 +/- 0.0013 h-1, of metildogixon, 0.0071 +/- 0.0007 h-1. The elimination rates correspond to half-lives of 80 h for digoxin and of 97 h for metildigoxin. From our investigations and published data a weighed mean of 47 ml/min was calculated for the extrarenal clearance of metildigoxin. This is not significantly different from the mean extrarenal clearance of 40 ml/min reported for digoxin. A total body clearance of 40 ml/min and a daily intravenous dose of 0.1 mg correspond to an average steady-state glycoside concentration of 1.74 ng/ml.
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SUMMARY Five healthy adult dogs were given a single iv dose (40 mg/kg of body weight) of ticarcillin disodium. Serum concentrations were measured serially over a period of 12 hours. Five days later, the drug was administered im to the dogs at the same dose rate, and serum concentrations were measured serially for 12 hours. The mean peak serum concentration after im administration was 120.5 μg/ml at 1.5 hours. Pharmacokinetic values following iv administration were (i) elimination rate constant = 0.8/hour -1 , (ii) half-life = 0.8 hour, (iii) serum clearance = 292 ml/hr/kg, and (iv) apparent volume of distribution = 347 ml/kg. Estimated values after im administration were (i) elimination rate constant = 0.6/hour, (ii) half-life = 1.1 hours, (iii) serum clearance = 218 ml/hr/kg, and (iv) apparent volume of distribution = 345 ml/kg; only the elimination rate constants were significantly different between the 2 routes of administration.
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