Pharmacokinetics of cimetidine in critically ill patients

Summary Cimetidine disposition was studied after rapid (1 min) intravenous infusion in eight critically ill patients aged between 20 years and 77 years; one patient was studied on two occasions. Cimetidine dose was 300 mg in seven patients and 400 mg in the remaining patient. Arterial plasma cimetidine concentrations at the end of the infusion were very high and ranged from approximately 15–35 mg/l. Pharmacokinetic parameters displayed wide interpatient variability (coefficients of variation of 30–50%) and significant relationships emerged between some of these parameters and certain patient characteristics. Most notable, total systemic plasma clearance of cimetidine was directly related to estimated creatinine clearance (p<0.01). This relationship might prove to be a useful method of individualizing cimetidine dosage in critically ill patients.     

Pharmacokinetics and pharmacodynamics of meropenem in critically ill patients

The pharmacokinetics and pharmacodynamics of meropenem were investigated in 14 critically ill patients with sepsis. Patients with creatinine clearance (CrCl) higher than 50 ml/min received 1 g meropenem three times daily (Group I) and patients with CrCl lower than 50 ml/min received 1 g meropenem twice daily (Group II). Meropenum concentrations in plasma were determined by high performance liquid chromatography with UV detection. The pharmacokinetic parameters differed between the two groups as follows, Group I, maximal concentration 56.3 +/- 19.1 microg/ml; trough concentration 3.3 +/- 2.5 microg/ml; elimination half life 2.5 +/- 1.2 h; clearance (Cl) 155.8 +/- 40.6 ml/min; MRT 2.2 +/- 0.4 h; steady state volume of distribution (V(ss)) 21.7 +/- 5.7 l, and AUC(-8) 119.4 +/- 32.6 microg/ml h. Group II, maximal concentration 71.1 +/- 5.1 microg/ml; trough concentration 3.4 +/- 1.8 microg/ml; elimination half life 3.9 +/- 1.6 h; Cl 77.7 +/- 15.8 ml/min; MRT 3.5 +/- 0.6 h; V(ss), 17.1 +/- 2.1 l, and AUC(0-12) 230.2 +/- 43.3 microg/ml h. The most frequently isolated bacteria from blood and wound infections were Acinetobacter baumanii, Pseudomonas aeruginosa, Klebsiella pneumoniae and Escherichia coli; their meropenem minimal inhibitory concentrations (MICs) ranged from 0.064 to 3.0 mg/l. In most cases the pharmacodynamic parameters, measured as T>MIC index, were higher than 75%. In both groups, patients with susceptible pathogens (MIC<1 mg/l) had meropenem plasma levels which exceeded the MIC for the whole dosing interval. When pathogens were highly resistant (A. baumanii or P. aeruginosa) the T>MIC indices were lower.     

Clinical pharmacodynamics of linezolid in seriously ill patients treated in a compassionate use programme

OBJECTIVE: To characterise the pharmacokinetic-pharmacodynamic relationships for linezolid efficacy. DESIGN AND STUDY POPULATION: Retrospective nonblinded analysis of severely debilitated adult patients with numerous comorbid conditions and complicated infections enrolled under the manufacturer's compassionate use programme. METHODS: Patients received intravenous or oral linezolid 600 mg every 12 hours. Plasma concentrations were obtained and a multicompartmental pharmacokinetic model was fitted. Numerical integration of the fitted functions provided the area under the concentration-time curve over 24 hours (AUC), the ratio of AUC to minimum inhibitory concentration (AUC/MIC) and the percentage of time that plasma concentrations exceeded the MIC (%T>MIC). MAIN OUTCOME MEASURES: Modelled pharmacodynamic outcomes of efficacy included probabilities of eradication and clinical cure (multifactorial logistic regression, nonparametric tree-based modelling, nonlinear regression) and time to bacterial eradication (Kaplan-Meier and Cox proportional hazards regression). Factors considered included AUC/MIC, %T>MIC, site of infection, bacterial species and MIC, and other medical conditions.RESULTS: There were 288 cases evaluable by at least one of the efficacy outcomes. Both %T>MIC and AUC/MIC were highly correlated (Spearman r2 = 0.868). In our analyses, within specific infection sites, the probability of eradication and clinical cure appeared to be related to AUC/MIC (eradication: bacteraemia, skin and skin structure infection [SSSI], lower respiratory tract infection [LRTI], bone infection; clinical cure: bacteraemia, LRTI) and %T>MIC (eradication: bacteraemia, SSSI, LRTI; clinical cure: bacteraemia, LRTI). Time to bacterial eradication for bacteraemias appeared to be related to the AUC, %T>MIC and AUC/MIC. For most sites, AUC/MIC and %T>MIC models performed similarly. CONCLUSIONS: Higher success rates for linezolid may occur at AUC/MIC values of 80-120 for bacteraemia, LRTI and SSSI. Chance of success in bacteraemia, LRTI and SSSI also appear to be higher when concentrations remain above the MIC for the entire dosing interval.     

Pharmacokinetics and pharmacodynamics of levofloxacin in critically ill patients with ventilator-associated pneumonia

The pharmacokinetics of levofloxacin and outcome of levofloxacin therapy in critically ill patients with ventilator-associated pneumonia (VAP) were assessed. Further theoretical considerations regarding the pharmacokinetic/pharmacodynamic (PK/PD) appropriateness of levofloxacin therapy were made. Twelve patients completed the study, all of whom were treated with a standard intravenous levofloxacin regimen (2x500 mg on Day 1, then 1x500 mg daily). The maximum free plasma levofloxacin concentration (fC(max,ss)) and the area under the free concentration-time curve (fAUC) were 8.13+/-1.64 mg/L and 49.63+/-15.60 mgh/L, respectively. Optimal PK/PD target parameters were achieved in 10 patients; clinical success was attained in 11 of the 12 patients who completed the study. Bacterial eradication was obtained in 9 of the 11 cases with microbiologically confirmed bacteriological aetiology. Intravenous levofloxacin therapy (500 mg/day) was proven to be an effective regimen in this limited number of patients with VAP. However, theoretical considerations based on PK/PD indices predict that, with the current susceptibility breakpoint of 2mg/L, even higher levofloxacin doses (e.g. 1000 mg) could result in treatment failures in infections caused by pathogens labelled as levofloxacin-susceptible in the microbiology report.     

Pharmacokinetics of intravenous omeprazole in critically ill paediatric patients

The proton pump inhibitors are first-line drugs for the treatment of a number of gastrointestinal diseases. These drugs have a good safety profile, making it possible to use them in paediatric patients. Although their pharmacokinetics in children has not been extensively studied, research performed suggests that the dose used should be varied as a function of age, as this factor affects the drug’s metabolism. Proton pump inhibitors can be used in critically ill children for the prophylaxis and treatment of gastrointestinal haemorrhage, although there is still little experience with this. The most widely used proton pump inhibitor at the present time is omeprazole. As there are specific characteristics of these patients that could alter the pharmacokinetics of the drugs, studies need to be performed to determine the most suitable dose and dosage interval.     

Pharmacokinetics and pharmacodynamics in the critically ill patient

1. Until recently, when drugs were used in critically ill patients they were expected to behave in the same way as in less seriously ill patients. Now the unpredictability of even the most reliable drugs has been recognized. With this there is an awareness of the adverse effects drugs may have on organs other than the ones the drug was intended to act on. In patients with multiorgan dysfunction, poly-pharmacy is usually needed. The drugs may not only interfere with the action of each other at the receptor and enzyme level, but may also change protein binding and elimination. All these effects may be unimportant in less seriously ill patients, but may affect outcome in the critically ill. A high degree of awareness and suspicion of unknown drug-induced adverse reaction is needed by clinicians and pharmacologists alike.     

Pharmacokinetics and pharmacodynamics of oral nizatidine

Nizatidine was studied in six high-acid-secretor (basal secretion, greater than or equal to 5 mEq/hr) male volunteers in a randomized, double-blind, nonbalanced, cross-over, placebo and standard drug-controlled study. Doses of 75 mg, 150 mg, and 300 mg bid were compared with placebo and cimetidine 300 mg qid. Nocturnal acid output was significantly reduced (P less than .01) by all doses of nizatidine (36 +/- 22, 36 +/- 31, and 26 +/- 20 mEq) with 75 mg, 150 mg and 300 mg, respectively, and also by cimetidine (43 +/- 39 mEq) as compared with placebo (101 +/- 61 mEq). Nizatidine also significantly reduced meal-stimulated acid secretion at breakfast (14 +/- 9, 9 +/- 7, and 5 +/- 6 mEq/2 hours with 75 mg, 150 mg, and 300 mg, respectively, P less than .01), at lunch (50 +/- 22, 57 +/- 22 and 50 +/- 35 mEq/2 hours, P less than .05) but did not have any effect at dinner (65 +/- 16, 78 +/- 24, and 71 +/- 17 mEq/2 hours) whereas cimetidine, given every 6 hours, significantly (P less than .01) reduced meal-stimulated acid secretion (25 +/- 16, 27 +/- 20 and 31 +/- 15 mEq/2 hours, breakfast, lunch, and dinner, respectively) as compared with placebo (81 +/- 30, 76 +/- 25, and 66 +/- 16 mEq/2 hours, breakfast, lunch, and dinner, respectively). Both drugs have a similar pharmacokinetic profile. Nizatidine seems to be a promising H2 antagonist, more potent than cimetidine (on an mg/mg basis), and efficacy studies on gastric acid disorders should be performed.     

Pharmacokinetics and pharmacodynamics of intravenous acetaminophen in neonates

Effective analgesia in neonates is still hampered owing to a lack of data on pharmacokinetics and pharmacodynamics of analgesics. In this article, the consecutive steps taken to document aspects of disposition (pharmacokinetics and metabolism) and safety (hepatic tolerance, hemodynamic stability and effects on body temperature) during exposure to intravenous acetaminophen in neonates are summarized. Based on these data, dosing suggestions were formulated. However, we have to be aware that such dosing suggestions are - at present - without any validated pharmacodynamic correlates since the applicability of a fixed acetaminophen target concentration (10 mg·l(-1)) in neonates of different subpopulations remains to be documented. In addition, the number of observations in extreme preterm neonates is limited. Finally, epidemiological data suggest a link between perinatal acetaminophen exposure and an increased risk to developing asthma. Consequently, well designed and appropriately powered pharmacodynamic studies in neonates are urgently required, with specific emphasis on extreme preterm neonates.     

Pharmacokinetics and pharmacodynamics of intravenous inotropic agents

Positive inotropic drugs have various mechanisms of action. Long-term use of cyclic adenosine monophosphate (cAMP)-dependent drugs has adverse effects on the prognosis of heart failure patients, whereas digoxin has neutral effect on mortality. There are, however, little data on the effects of intravenous inotropic drugs on the outcome of patients. Intravenous inotropic agents are used to treat cardiac emergencies and refractory heart failure. beta-Adrenergic agonists are rapid acting and easy to titrate, with short elimination half-life. However, they increase myocardial oxygen consumption and are thus hazardous during myocardial ischaemia. Furthermore they may promote myocyte apoptosis. Phosphodiesterase (PDE) III inhibiting drugs (amrinone, milrinone and enoximone) increase contractility by reducing the degradation of cAMP. In addition, they reduce both preload and afterload via vasodilation. Short-term use of intravenous milrinone is not associated with increased mortality, and some symptomatic benefit may be obtained when it is used in refractory heart failure. Furthermore, PDE III inhibitors facilitate weaning from the cardiopulmonary bypass machine after cardiac surgery. Levosimendan belongs to a new group of positive inotropic drugs, the calcium sensitisers. It has complex pharmacokinetics and long-lasting haemodynamic effects as a result of its active metabolites. In comparative trials, it has been better tolerated than the most widely used beta-agonist inotropic drug, dobutamine. The pharmacokinetics of the intravenous inotropic drugs might sometimes greatly modify and prolong the response to the therapy, for example because of long-acting active metabolites. These drugs display considerable differences in their pharmacokinetics and pharmacodynamics, and the selection of the most appropriate inotropic drug for each patient should be based on careful consideration of the clinical status of the patient and on the pharmacology of the drug.     

Pharmacokinetics and pharmacodynamics of intravenous levofloxacin in patients with early-onset ventilator-associated pneumonia

OBJECTIVE: To investigate the pharmacokinetics of levofloxacin and the pharmacokinetic-pharmacodynamic appropriateness of its total body exposure in patients in the intensive care unit (ICU) treated for early-onset ventilator-associated pneumonia (VAP) with intravenous levofloxacin 500mg twice daily. DESIGN: Prospective non-blinded pharmacokinetic-pharmacodynamic study. PARTICIPANTS: Ten critically ill adult patients with normal renal function. METHODS: Blood and urine samples were collected at appropriate times during a 12-hour administration interval at steady state. Levofloxacin concentrations were determined by high-performance liquid chromatography. Clinical and microbiological outcomes were assessed. RESULTS: Levofloxacin pharmacokinetics were only partially comparable with those obtained from literature data for healthy volunteers. Area under the concentration-time curve (AUC(tau)) over the 12-hour dosage interval was about 30-40% lower than in healthy volunteers (33.90 vs 49.60 mg. h/L). The reduced exposure may be due to a greater clearance of levofloxacin (0.204 vs 0.145 L/h/kg [3.40 vs 2.42 mL/min/kg]), leading to a shorter elimination half-life (5.2 vs 7.6 hours). Cumulative urinary excretion during the 12-hour dosage interval confirmed the greater excretion of unchanged drug in these patients compared with healthy subjects (76% vs 68%). Coadministered drugs used to treat underlying diseases (dopamine, furosemide, mannitol) may at least partially account for this enhanced elimination in critically ill patients. Intravenous levofloxacin 500mg twice daily ensured a median C(max)/MIC (maximum plasma concentration/minimum inhibitory concentration) ratio of 102 and a median 24-hour AUC/MIC ratio of 930 SIT(-1). h (inverse serum inhibitory titre integrated over time) against methicillin-sensitive Staphylococcus aureus and Haemophilus influenzae. The overall success rate of the assessable cases was 75% (6/8). Bacterial eradication was obtained in all of the assessable cases (8/8), but a superinfection (Acinetobacter anitratus,Pseudomonas aeruginosa) occurred in three cases. CONCLUSIONS: The findings support the suitability of intravenous levofloxacin 500mg twice daily in the treatment of early-onset VAP in ICU patients with normal renal function. Levofloxacin may represent a valid alternative to non-pseudomonal beta-lactams or aminoglycosides in the empirical treatment of early-onset VAP. However, further larger studies are warranted to investigate its efficacy.     

Pharmacokinetics and pharmacodynamics of CI-992 following intravenous and oral administration to cynomolgus monkeys

The purpose of this study was to characterize CI-992 pharmacokinetics and pharmacokinetics/pharmacodynamics (PK/PD) in sodium deplete monkeys. Panels of monkeys were administered CI-992 as a 1 h intravenous infusions (0.1 and 1 mg kg⁻¹) or as single oral doses (0, 10, 50, and 100 mg kg⁻¹). Mean arterial blood pressure (MABP) was monitored and serial blood samples were collected up to 24 h postdose. Plasma CI-992 concentrations were quantitated by radioimmunoassay. Pharmacokinetic parameters were calculated by noncompartmental methods. PK/PD relationships were assessed by standard methods. Oral bioavailability of CI-992 in the monkeys was <2%; steady-state volume of distribution was 0.67 L kg⁻¹; clearance was 10.4 mL min⁻¹ kg⁻¹. Following oral administration, t_max generally occurred 6–9 h postadministration; plasma CI-992 concentrations increased with increasing dose between 10 and 50 mg kg⁻¹, but did not change appreciably from 50 to 100 mg kg⁻¹. After intravenous administration, change in MABP was correlated with plasma CI-992 concentration through an effect compartment model in which the maximum achievable effect was a 22 mm Hg decrease in MABP; the steady-state concentration which produced half the maximum effect was 11 ng mL⁻¹. Following the 10 mg kg⁻¹ oral dose the maximum decrease in MABP was 19.1 mm Hg; higher doses did not produce greater maximum response but increased the duration of action. In contrast to observations following intravenous administration, a trend for decreasing MABP with increasing plasma CI-992 was not apparent following oral CI-992 administration. © 1998 John Wiley & Sons, Ltd.     

Pharmacokinetics and pharmacodynamics of intravenous cibenzoline in normal volunteers

The pharmacokinetics of intravenous (IV) cibenzoline were studied in six healthy male volunteers ranging in age from 51 to 78 years. The subjects received intravenous (IV) cibenzoline 100 mg over 20 minutes, and plasma and urine specimens were collected for 48 hours. Cibenzoline plasma concentrations at the end of the infusion ranged from 730 to 1,420 ng/mL and exhibited triexponential decline thereafter. The following mean model independent pharmacokinetic parameters were calculated from the plasma and urine concentration data: terminal half-life, 9.8 hours (range, 8.5-11.9); plasma clearance, 523 mL/min (range, 387-687); volume of distribution, 445 L (range, 328-506); and renal clearance, 289 mL/min (range, 202-334). Approximately 31% to 59% of the dose was recovered unchanged in the urine in 48 hours. A triexponential pharmacokinetic equation with zero order input was used to curve fit the plasma and urine data, and the model-dependent parameters agreed well with the model-independent estimates. A hysteresis loop was observed in the relationship between cibenzoline plasma concentration and QRS prolongation, indicating an initial lag between plasma concentration and effect after IV administration. Based on these results, the following preliminary dosing regimen was proposed to rapidly achieve and maintain therapeutic plasma concentrations equal to or slightly greater than 200-400 ng/mL: 0.25 mg/kg/min IV bolus over one minute followed by 1-1.5 mg/kg/hr for one hour and 0.2-0.4 mg/kg/hr for long-term infusion.     

Pharmacokinetics and pharmacodynamics following intravenous doses of azimilide dihydrochloride

Azimilide pharmacokinetics and pharmacodynamics were characterized in a safety and tolerance study of intravenously administered azimilide dihydrochloride. This was a parallel-group design (seven treatments), and 68 healthy volunteers received the drug. Single intravenous infusion doses (4.5 to 9 mg/kg) were administered over 60 minutes, and single 4.5 mg/kg intravenous infusion doses were also given over 15 or 30 minutes. Blood and urine specimens were collected and analyzed for azimilide and metabolites. QTc was measured as a marker of class III antiarrhythmic activity. Azimilide pharmacokinetics were dose proportional and did not differ among infusion rates. Azimilide pharmacodynamics did not differ among treatments. Mean Emax ranged from 23 to 28% delta QTc, with mean EC50 of 509 to 566 ng/mL. Peak circadian variation in QTc was equivalent to 14% of Emax. Rapid equilibration occurred between blood and the biophase. Unconfounded pharmacodynamic estimates required inclusion of circadian QTc variation in the pharmacodynamic model.     

健康受试者口服氟罗沙星的药动学/药效学研究

目的:研究健康受试者口服氟罗沙星的药动学(PK)和药效学(PD),从而优化氟罗沙星的临床给药方案。方法:采用三周期自身交叉对照的方式对15名健康受试者分别口服200,300,400 mg氟罗沙星片后,以高效液相色谱法(HPLC)测定血药浓度,进而求出药动学(PK)参数。体外药效学(PD)研究是测定氟罗沙星对临床分离的15种494株常见致病菌的最低抑菌浓度(MIC)。以AUC_0-24/MIC作为氟罗沙星的PK/PD参数(靶值为100和125),采用蒙特卡洛(Monte Carlo)模拟评价氟罗沙星的3种治疗方案对不同分离菌株AUC_0-24/MIC值的药效学累积反应分数(CFR)。结果:以CFR> 90%作为抗感染经验治疗的合理选择,对于大肠杆菌和淋球菌引起的感染,或口服200 mg(qd)即可;对硝酸盐阴性杆菌、肠杆菌属和哈夫尼亚菌属引起的感染,或口服300 mg(qd)即可;对于表葡球菌、铜绿假单胞菌、志贺菌属、肺炎克雷伯杆菌、柠檬酸杆菌属、普通变形杆菌、肺炎链球菌、沙门菌属和金葡球菌(MSSA)引起的感染,或口服400 mg(qd)可获得预期满意的临床疗效并能有效预防细菌耐药性产生,而对于耐甲氧西林金葡菌(MRSA),PK/PD参数显示疗效不佳。结论:应用Monte Carlo模拟评价氟罗沙星的PK/PD参数,可以为氟罗沙星的临床最佳给药方案的制定提供参考依据。     

Pharmacokinetics of intravenous and oral levofloxacin in critically ill adults in a medical intensive care unit

STUDY OBJECTIVE: To characterize the pharmacokinetic disposition of intravenous and oral levofloxacin in critically ill adults. DESIGN: Prospective, open-label study. SETTING: University teaching hospital. PATIENTS: Thirty critically ill patients in a medical intensive care unit (ICU). INTERVENTIONS: All patients received levofloxacin as part of their routine medical care. Pharmacokinetic evaluations were performed in 28 patients receiving intravenous levofloxacin. Ten of these patients subsequently were switched to oral levofloxacin and underwent a second pharmacokinetic evaluation during oral therapy. MEASUREMENTS AND MAIN RESULTS: Mean +/- SD levofloxacin half-life, clearance at steady state, and volume of distribution in all 28 patients were 8.0 +/- 1.7 hours, 134 +/- 35 ml/minute, and 1.2 +/- 0.3 L/kg, respectively Maximum and minimum serum concentrations (Cmax and Cmin) and area under the serum concentration-time curve from 0-24 hours (AUC(0-24)) in patients receiving levofloxacin 500 mg intravenously were 7.5 +/- 0.8 mg/L, 1.0 +/- 0.5 mg/L, and 66.1 +/- 15.7 mg x hour/L, respectively Observed Cmax, Cmin, and time at which maximum concentration was achieved after oral doses of levofloxacin 500 mg were 5.5 +/- 1.1 mg/L, 0.8 +/- 0.4 mg/L, and 1.3 +/- 0.4 hours, respectively. These values were significantly different (p < 0.05) from those observed after intravenous dosing in the same patients; other pharmacokinetic parameters were similar. Statistically significant increases (p < 0.05) in Cmax, Cmin, half-life, and AUC(0-24) were found in critically ill patients administered multiple doses of intravenous levofloxacin compared with historical data from healthy volunteers. CONCLUSIONS: The dosage regimen of intravenous levofloxacin 500 mg once/day appears adequate for most pathogens found in critically ill patients with normal renal function. Less susceptible pathogens may require an increased daily dose for more optimal therapy. Orally administered levofloxacin appears to be well absorbed in selected ICU patients and has pharmacokinetics similar to those of intravenously administered levofloxacin.     

Pharmacokinetics of intravenous and oral tolmesoxide

Summary A high pressure liquid chromatographic assay was developed for simultaneous measurement of the plasma levels of tolmesoxide and its principal metabolite, RX71112. The assay was used to study the disposition of intravenous and oral tolmesoxide in ten normotensive subjects. Two exponential terms were required to describe the disposition of the drug following intravenous administration, whilst a single exponential term sufficied to account for the decay in the plasma concentration after oral administration. The bioavailability of oral tolmesoxide from capsules averaged 84.5% and was independent of dose. The mean half-life after i. v. dosing was 2.6 h (±0.3 SEM) compared to values of 1.9 h (±0.1 SEM) and 2.7 h (±0.5 SEM) following 200 and 400 mg oral doses respectively. In all subjects RX71112 appeared in plasma shortly after tolmesoxide following both routes of administration. The terminal half-life of the metabolite was significantly longer than tolmesoxide with a mean value of 4.9 h (±0.9 SEM) following the 200 mg oral dose of tolmesoxide. The binding of tolmesoxide and RX71112 at therapeutic plasma concentration was 36.8% (±0.5 SEM) and 58.5% (±0.3 SEM) and this remained unchanged at higher concentrations.     

Pharmacokinetics of intravenous trovafloxacin in critically ill adults

The pharmacokinetic disposition of numerous antimicrobial agents is altered in critically ill patients. Pharmacokinetics of trovafloxacin, a fluoroquinolone indicated specifically for severe, life-threatening infections in the intensive care unit, have not been well studied in this population. We characterized the pharmacokinetic disposition of trovafloxacin after administration of alatrofloxacin, the intravenous prodrug, in critically ill adults. Seven patients (3 men, 4 women; mean +/- SD age 59.4 +/- 20.6 yrs; baseline aspartate aminotransferase [AST]/alanine aminotransferase [ALT] 66.0 +/- 40.6/51.5 +/-37.5 IU/L; median Acute Physiology and Chronic Health Evaluation [APACHE II] score 27, range 15-32) were studied at estimated steady state. Calculated (mean +/- SD) half-life, clearance at steady state, and volume of distribution in all patients were 10.9 +/- 1.8 hours, 161.3 +/- 41.1 ml/minute, and 1.4 +/- 0.4 L/kg. In patients receiving 300 mg, maximum concentration, minimum concentration, and area under the curve from 0-24 hours were 3.6 +/- 0.5 mg/L, 0.6 +/- 0.3 mg/L, and 34.2 +/- 10.6 mg x hr/L, respectively. These results are consistent with published values in other patient populations, indicating that trovafloxacin pharmacokinetics are not substantially altered in critically ill patients with normal or mildly impaired hepatic function.     

Pharmacokinetics of intravenous and oral chlordesmethyldiazepam in patients on regular haemodialysis

Summary The pharmacokinetics of a single 2 mg IV dose of chlordesmethyldiazepam has been studied in 11 patients with renal failure on regular haemodialysis and in 11 age-matched healthy controls. The kinetics was also examined after a single 2 mg oral dose in 6 of the 11 renal failure patients.After intravenous administration the kinetics of total chlordesmethyldiazepam in renal patients and controls were the same. The unbound fraction of the drug in renal patients was higher (5.5%) than in controls (2.9%). Correction for differences in protein binding revealed a reduced apparent volume of distribution (47 vs. 140 l · kg^–1) and a reduced clearance (5.0 vs. 10.5 ml · min^–1 · kg^–1) in the patients. The systemic availability of oral chlordesmethyldiazepam was good (82%) despite a relatively slow absorption rate.     

Pharmacokinetics and pharmacodynamics of intravenous trasemide in mutant Nagase analbuminemic rats

The importance of plasma protein binding of intravenous furosemide in circulating blood for its urinary excretion and hence its diuretic effects in mutant Nagase analbuminemic rats (NARs, an animal model for human familial analbuminemia) was reported. Based on the furosemide report, the diuretic effects of another loop diuretic, torasemide, could be expected in NARs if plasma protein binding of torasemide is considerable in the rats. This was proven by this study. After intravenous administration of torasemide, 10 mg/kg, to NARs, the plasma protein binding of torasemide was 23.3% in the rats due to binding to alpha- and beta-globulins (this value, 23.3%, was greater than only 12% for furosemide), and hence the percentages of intravenous dose of torasemide excreted in 8-h urine as unchanged drug was 14.9% in the rat (this value was considerably greater than only 7% for furosemide). After intravenous administration of torasemide to NARs, the AUC (301 versus 2680 microg/min/ml) was significantly smaller [due to significantly faster both Cl(r) (4.81 versus 0.386 ml/min/kg) and Cl(nr) (28.3 versus 3.33 ml/min/kg)], terminal half-life (18.3 versus 73.5 min) and mean residence time (6.97 versus 61.8 min) were significantly shorter (due to faster Cl, 33.2 versus 3.74 ml/min/kg), and amount of 8-h urinary excretion of unchanged torasemide (446 versus 323 microg, due to increase in intrinsic renal excretion) was significantly greater than those in control rats. The 8-h urine output and 8-h urinary excretions of sodium and chloride were comparable between two groups of rats although the 8-h urinary excretion of torasemide was significantly greater in NARs. This could be explained by the following. The amount of urinary excretion of torasemide was significantly greater in NARs than that in control rats only between 0 and 30 min urine collection. In both groups of rats, the urinary excretion rate of torasemide during 0-30 min reached an upper plateau with respect to urine flow rate as well urinary excretion rates of sodium and chloride. Therefore, the diuretic effects (8-h urine output and 8-h urinary excretions of sodium and chloride) were not significantly different between the two groups of rats.     

Pharmacokinetics and pharmacodynamics of physostigmine in the rat after intravenous administration

The time course of physostigmine (Phy) and metabolites in plasma, brain, and muscle, the inhibition of butyrylcholinesterase (BuChE) in plasma, and cholinesterase (ChE) activity in brain and muscle were studied in rat after iv bolus administration of 3H-Phy (100 micrograms/kg). The semilogarithmic plot of plasma Phy concentration versus time indicates a biphasic decline. These data were analyzed by nonlinear computer fitting program (PC-NONLIN) using a two-compartment open model with bolus input and first order elimination. The pharmacokinetic constants A, B, alpha, beta, AUC, K10 half-life, alpha-half-life, beta-half-life, K10, K12, and K21 were obtained. The alpha-half-life and the beta-half-life were 1.31 and 15.01 min, respectively. The apparent volume of distribution was found to be 270 ml. The clearance was 12.43 ml min-1. The half-life of Phy in brain was 11 min. The brain to plasma ratio (1.69) peaked at 15 min. Phy is metabolized to eseroline and three other metabolites, M1, M2, and M3. The distribution studies showed that the radioactivity per g of tissue was highest in kidney and liver, whereas the percentage of the administered dose in terms of radioactivity was maximum in muscle followed by liver. The maximum inhibition of BuChE (52%) correlates with the highest Phy concentration (84.6 ng/ml) in plasma at 2 min and 70% of the enzymic activity recovered by 45 min. The maximum inhibition of ChE (63%) in the brain correlates with the highest Phy concentration (128 ng/g) at 3 min, and 85% of the enzymic activity was recovered within an hour.(ABSTRACT TRUNCATED AT 250 WORDS)