Pharmacokinetics of tinidazole in chronic renal failure and in patients on haemodialysis.

The pharmacokinetics of tinidazole after infusion (800 mg in 15 min) were studied in 12 patients with chronic renal failure (RI) and in five patients undergoing regular dialysis treatment (RD). Tinidazole elimination plasma half-life was 15.09 +/- 0.68 h (mean +/- s.e. mean) (RI) and 12.9 +/- 1.0 h after dialysis (RD), but there was a significant decrease in half-life during dialysis (4.25 +/- 0.43 h) P less than 0.001). The apparent volume of distribution (0.64 +/- 0.03 l/kg) was equal to extra and intracellular water volume and tinidazole was little bound to plasma protein (8%). There was a slight sex difference in apparent volume of distribution between male patients (0.70 +/- 0.09 l/kg) and female patients (0.59 +/- 0.10 l/kg) (P = 0.07), but as body clearance decreases in the same order, there was no modification of plasma half-life. In renal failure, pharmacokinetics of tinidazole were not disturbed because no correlation between half-life, body clearance and creatinine clearance occurred; urine elimination was about 7% of administered dose. Plasma clearance during dialysis was 49.9 +/- 3.2 ml/min and about 43% of the available drug was eliminated during the 6 h dialysis procedure. These results suggest that an additional half-dose infusion should be given after the end of dialysis in patients undergoing regular dialysis treatment.     

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.     

Pharmacokinetics of recombinant human superoxide dismutase.

Superoxide dismutase (SOD) disposition was studied in order to design a rational approach for drug administration in the setting of acute myocardial infarction. Four chronically instrumented conscious dogs received the following dosage regimens of recombinant human SOD (rhSOD) on successive days: (a) 5 mg/kg left atrial (LA) bolus, (b) 5 mg/kg central vein (CV) bolus, (c) 15 mg/kg CV bolus, and (d) 5 mg/kg CV infusion over 60 min; additionally, all dogs received (e) a 5 mg/kg CV bolus under pentobarbital anesthesia. Serial serum samples were obtained after each dose and serial myocardial samples were obtained after dose (e). The serum rhSOD concentration was measured by radioimmunoassay and the data were fit to a two-compartment model. The distribution half-life was 7.8 +/- 1.7 min (mean +/- SEM), and the elimination half-life was 51.1 +/- 5.9 min; the central compartment volume of distribution (Vc) was 81 +/- 26 ml/kg and the steady-state volume of distribution was 156 +/- 20 ml/kg. The dosage regimen had no influence on clearance rates. Peak plasma concentrations (micrograms/ml) for the dosage regimens were (a) 65 +/- 28, (b) 89 +/- 19, (c) 214 +/- 61, (d) 20 +/- 5, and (e) 86 +/- 9. The peak level following continuous infusion did not occur until 50 min of infusion and was only one-fourth of the level achieved with a bolus of the same dose. Myocardial levels were less than 1% of serum levels, suggesting negligible rhSOD penetration into the myocardium.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

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)].     

Pharmacokinetics and pharmacodynamics of flestolol, a new short-acting, beta-adrenergic receptor antagonist

The pharmacokinetics and pharmacodynamics of flestolol, a new short-acting, beta-adrenergic receptor antagonist, were examined in nine healthy subjects after a constant intravenous infusion of 5 micrograms/kg/min for 72 hours. Flestolol blood levels were determined by high-performance liquid chromatography. In all subjects, flestolol blood concentration attained steady state 30 minutes after initiation of infusion. The mean +/- standard deviation steady-state concentration of flestolol was 31.1 +/- 12.0 ng/mL. The elimination half-life averaged 7.2 minutes. The mean +/- standard deviation total body clearance was 181 +/- 66 mL/min/kg. The apparent volume of distribution and the area under the curve averaged 1.89 L/kg and 2.23 micrograms-hr/mL, respectively. Flestolol did not cause any significant change (P greater than .05) in the heart rate or systolic or diastolic blood pressure from the baseline. Flestolol significantly (P less than .05) attenuated the isoproterenol-induced increase in heart rate and systolic blood pressure and decrease in diastolic blood pressure in comparison with baseline. The average maximum reduction in isoproterenol tachycardia was in the range of 63% to 79% during flestolol infusion. There was a rapid recovery from beta blockade after termination of flestolol infusion; the recovery averaged 96% 20 minutes after the infusion was stopped. We conclude that flestolol exhibits a very short half-life and is cleared mainly by extrahepatic routes. It is an effective beta blocker and possesses a short duration of action.     

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.     

Invasion and distribution of methanol

After the enzyme systems responsible for methanol oxidation were blocked by ethanol, five test persons were given methanol at a dose of approximately 10 mg/kg weight, once orally and once parenterally. Taking into account the endogenous blood methanol levels detectable before the administration of methanol, C0 concentrations of 11.1-15.9 mg/kg were reached. This corresponds to a distribution volume of approximately 0.77 +/- 0.07 l/kg, which is comparable to the 0.78 +/- 0.09 l/kg obtained for ethanol. After parenterally administering methanol as a bolus, the distribution half-life was on average 8 min (range: 3.8-13.8 min). After oral administration of methanol diluted in 100 ml water on an empty stomach, invasion took place with a half-life of approximately 5 min (3.8-6.9 min). In one case, however, due to vegetative disturbances the invasion half-life was 23.1 min.     

Enzyme replacement in Fabry disease: pharmacokinetics and pharmacodynamics of agalsidase alpha in children and adolescents

This multicenter, open-label study evaluated pharmacokinetics, pharmacodynamics, and safety of agalsidase alpha in pediatric compared with adult patients with Fabry disease. The pharmacokinetic parameters of pediatric patients (19 boys, 5 girls, 6-18 years old; mean age, 11.8 years) were compared to those of adult male and female patients who participated in other clinical studies. All patients received agalsidase alpha at a dose of 0.2 mg/kg infused over 40 minutes every other week. Agalsidase alpha exhibited a biphasic serum elimination profile with a maximum serum concentration at the end of the 40-minute infusion; <1% of the maximum concentration was detected 8 hours after dosing. In children, serum clearance was 2.0 to 9.4 mL/min/kg and tended to decrease with increasing age. The average clearance in children, 3.7 +/- 1.5 mL/min/kg (mean +/- SD), was significantly greater than that measured in 33 adults (2.3 +/- 0.7 mL/min/kg, P < .0001). Mean terminal elimination half-life of agalsidase alpha was prolonged in week 25 compared with baseline (150 vs 66 minutes) in 8 of 19 male children. The magnitude of the reduction of plasma globotriaosylceremide was similar in all age groups and was independent of area under the curve and other pharmacokinetic parameters. Except for clearance in younger patients, agalsidase alpha appears to have comparable pharmacokinetic and pharmacodynamic profiles in pediatric and adult Fabry patients of both genders.     

Pharmacokinetics and tissue concentrations of cefazolin in pediatric patients undergoing gastrointestinal surgery

Limited information is available on the pharmacokinetics and tissue penetration of cefazolin in pediatric patients. Nine children (age 0.8-10 years) undergoing gastrointestinal operations were studied. A single dose of cefazolin, 15-26 mg/kg was given i.v. over 2-3 min at the time of induction of anaesthesia. Multiple (5-8) blood samples were collected during the operative procedure and in the recovery room. Tissue samples from the rectus abdominis muscle were obtained at the time of incision, during surgery, and at closure. The concentration of cefazolin was measured by a high performance liquid chromatographic method. Peak serum concentrations of cefazolin ranged from 85.8-269.4 mcg/ml. Serum and tissue concentrations at incision were 50.5-169.9 mcg/ml and 1.8-29.7 mcg/g; at closure the serum and tissue concentrations ranged from 17.3-60.9 mcg/ml and 1.19-29.70 mcg/g, respectively. Total clearance, apparent distribution volume, and elimination half-life of cefazolin were 1.43 +/- 0.54 ml/min/kg, 0.08 +/- 0.03 l/kg, and 1.68 +/- 0.55 h respectively. Tissue concentrations of cefazolin were maintained above its minimum inhibitory concentrations against common susceptible pathogens. Hence, the current dosing regimen of cefazolin is adequate to protect against infection in pediatric patients undergoing gastrointestinal surgery.     

Bioavailability and mammary excretion of bisphenol a in Sprague-Dawley rats.

This study reports the absolute oral bioavailability and mammary excretion of bisphenol A in rats. The oral bioavailability was determined after administration of relatively low iv (0.1 mg/kg) and oral (10 mg/kg) doses of bisphenol A to rats. After iv injection, serum levels of bisphenol A declined biexponentially, with the mean initial distribution and terminal elimination half-lives being 6.1 +/- 1.3 min and 52.5 +/- 2.4 min, respectively. The systemic clearance (Cls) and the steady-state volume of distribution (Vss) averaged 107.9 +/- 28.7 m/min/kg and 5.6 +/- 2.4 L/kg, respectively. Upon oral administration, the maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 14.7 +/- 10.9 ng/ml and 0.2 +/- 0.2 h, respectively. The apparent terminal elimination half-life of bisphenol A (21.3 +/- 7.4 h) after oral administration was significantly longer than that after iv injection, indicating the flip-flop of the absorption and elimination rates. The absolute oral bioavailability of bisphenol A was low (5.3 +/- 2.1%). To determine the extent of mammary excretion, bisphenol A was given by simultaneous iv bolus injection plus infusion to steady state at low, medium, and high doses. The steady-state serum levels of bisphenol A were linearly increased with higher dosing rates. The systemic clearance (mean range, 119.2-154.1 ml/min/kg) remained unaltered over the dosing rate studied. The levels of bisphenol A in milk exceeded those in serum, with the steady-state milk to serum concentration ratio being 2.4-2.7.     

The stereoselective disposition of disopyramide in the dog

The disposition of d-, 1-, and d,1-disopyramide was studied in 5 conscious dogs after intravenous administration (15 mg/kg) of each compound using a balanced crossover design. The clearance of d-disopyramide (15.4 +/- 5.10 ml/min/kg) was significantly greater than that of the l-isomer (9.45 +/- 2.52 ml/min/kg) (p < 0.001). The clearance of the d,1-mixture was intermediate between that obtained for the d- and l-isomers. The steady-state volume of distribution of the three compounds was similar (approximately 1.4 liters/kg). The elimination half-life reflected differences in clearance, being 76.4 +/- 7.30 min for d-disopyramide, 112 +/- 23.4 min for 1-disopyramide, and 97.2 +/- 15.1 min for d,1-disopyramide. The effect of general anesthesia with urethane and chloralose on the disposition of the compounds was also examined. General anesthesia decreased the clearance and increased the half-life of all three compounds. No consistent differences in the volume of distribution were observed with anesthesia as compared to control. Thus, there is stereoselective elimination of the optical isomers of disopyramide in the dog, and general anesthesia decreases the clearance of d-, 1-, and d,1-disopyramide.     

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)     

Deuterium isotope effect on the toxicokinetics of monomethylamine in the rat

The single-dose toxicokinetics of monomethylamine has been characterized in the rat by HPLC assay of serial blood samples. Biphasic first-order elimination was observed following an iv bolus dose of 19 mumol/kg with a terminal half-life of 19.1 +/- 1.3 min (mean +/- SE, N = 4). The apparent steady state volume of distribution, systemic blood clearance, and renal blood clearance were 1.21 +/- 0.09 liter/kg, 53.4 +/- 3.5 ml/min/kg, and 5.72 +/- 0.53 ml/min/kg, respectively. The administration of an intragastric dose permitted the calculation of the systemic bioavailability of monomethylamine as 69 +/- 3%. Duplicate experiments using the structural analogue with deuterium atoms substituted for hydrogens on the methyl group revealed a much slower elimination of the compound, although ultimately, 5 times as much was excreted unchanged in the urine. Isotope effects calculated as the ratios of terminal half-life, systemic blood clearance, and systemic bioavailability were 1.9, 2.2, and 1.8, respectively.     

Disposition of valproic acid in maternal, fetal, and newborn sheep. I: placental transfer, plasma protein binding, and clearance.

Separate 24-h maternal and fetal infusions of valproic acid (VPA) were administered to five pregnant sheep at 125 to 138 days gestation (term approximately 145 days) to determine maternal-fetal disposition. The pharmacokinetics of VPA were also investigated in five newborn 1-day-old lambs after a 6-h drug infusion. Plasma, urine, and amniotic and fetal tracheal fluid samples were analyzed for VPA using gas chromatography-mass spectrometry. During maternal drug infusion, the average steady-state fetal/maternal unbound VPA plasma concentration ratio was 0.81 +/- 0.09. Unbound maternal-to-fetal VPA placental clearance (69.0 +/- 20.2 ml/min/kg) was similar to that in the other direction (61.9 +/- 24.2 ml/min/kg); this indicates passive placental diffusion and intermediate placental permeability of VPA in sheep. Newborn unbound VPA clearance (0.66 +/- 0.28 ml/min/kg) was much lower than in the mother (5.4 +/- 2.7 ml/min/kg) or the fetus (62.1 +/- 22.4 ml/min/kg), and exhibited pronounced Michaelis-Menten characteristics. The elimination half-life of the drug was much longer in the newborn (18.6 +/- 2.6 h) relative to the mother (5.6 +/- 1.4 h) and the fetus (4.6 +/- 1.9 h). Thus, VPA elimination in newborn lambs is much slower as compared with adult sheep, a situation similar to that in humans. Plasma protein binding of VPA was saturable, with similar VPA binding capacities and affinities in maternal and fetal plasma. VPA was extensively displaced from binding sites in the newborn lamb during the first 1 to 2 days of life, possibly because of increased plasma free fatty acid concentrations at birth. Thereafter, newborn plasma appeared to have a similar VPA binding capacity but lower affinity compared with the mother and the fetus.     

Pharmacokinetics of mexiletine and its metabolites, hydroxymethylmexiletine and p-hydroxymexiletine, after single oral administration in healthy subjects

Pharmacokinetics of mexiletine and its major metabolites, p-hydroxymexiletine and hydroxymethylmexiletine, were studied in 10 healthy subjects after administration of a single oral 400 mg dose. Mexiletine was extensively metabolized to hydroxymethylmexiletine and less to p-hydroxymexiletine. Mean metabolic ratio (Rm) was 0.54 and 0.18 respectively. Peak serum concentrations (Cmax) for mexiletine (0.686 +/- 0.110 micrograms/ml), hydroxymethylmexiletine (0.507 +/- 0.087 micrograms/ml), and p-hydroxymexiletine (0.096 +/- 0.046 micrograms/ml) occurred after 3.0, 4.0 and 4.2 +/- 0.6 h. Disposition parameters for mexiletine were as follows: volume of distribution (V lambda), 5.44 +/- 1.44 l/kg; serum clearance (CL) 8.08 +/- 1.23 ml/min/kg. There were no significant differences in elimination half-life (t1/2) and mean residence time (MRT) for mexiletine and its metabolites. Double-peak phenomenon was observed for all the subjects on elimination phase of mexiletine, hydroxymethylmexiletine and p-hydroxymexiletine.     

Pharmacokinetics of cyclophosphamide in Kenyan Africans.

The pharmacokinetics of cyclophosphamide was studied in 10 Kenyan Africans with Hodgkins lymphoma. The mean +/- s.d. elimination half-life (t1/2) was 7.5 +/- 1.38 h. The mean +/- s.d. volume of the central compartment (V1) was 0.35 +/- 0.12 l/kg and the apparent volume of distribution (V) was 0.64 +/- 0.06 l/kg. The microconstants k21, k12 and k10 were 1.81 +/- 0.84 h-1, 1.90 +/- 1.080 h-1 and 2.05 +/- 0.86 h-1 respectively (mean +/- s.d.).     

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.     

Amikacin pharmacokinetics in patients with spinal cord injury

The influence of chronic (greater than 1 yr duration) spinal cord injury (SCI) on the disposition of amikacin was studied in seven healthy subjects with SCI (five paraplegic, two tetraplegic) and seven able-bodied controls (intact neuraxes). The time course of amikacin serum concentration after a 30-minute infusion (7.5 mg/kg) was followed for up to 8.5 hours using fluorescence polarization immunoassay. Pharmacokinetic values were estimated by a noncompartmental analysis (NC). Amikacin steady-state volume of distribution (Vss) was increased to 0.20 +/- 0.04 l/kg (mean +/- SD) as compared to 0.17 +/- 0.02 l/kg in able-bodied controls (p 0.03), and its mean terminal elimination half-life in patients with SCI was prolonged by 0.64 hours over the control value of 2.11 +/- 0.27 hours (p 0.01). The NC estimated mean residence time (MRT) in patients with SCI (3.65 +/- 0.75 hrs) was 0.89 hours longer than that observed in controls (p 0.03). Our data suggest that the Vss, half-life, and MRT of amikacin are increased in persons with chronic SCI. As a result, amikacin dosing regimens developed in able-bodied humans may demonstrate diminished efficacy when extrapolated uncritically to these patients.