The pharmacokinetics of theophylline and enprofylline in patients with liver cirrhosis and in patients with chronic renal disease

Summary We have studied the pharmacokinetics of theophylline and enprofylline in patients with liver cirrhosis, patients with chronic renal failure, and healthy subjects, and have assessed the predictive value of routine tests of liver function and renal function (creatinine clearance) for theophylline and enprofylline total body clearances.Theophylline clearance was significantly decreased in the patients with liver cirrhosis compared with both the patients with renal failure and the healthy subjects (the mean values in the three groups were 24, 47, and 46 ml·h^–1·kg^–1 respectively.Enprofylline clearance was significantly decreased in the patients with chronic renal failure, compared with both the patients with liver cirrhosis and the healthy subjects (the values in the three groups were 64, 250, and 289 ml·h^–1·kg^–1 respectively.There was a strong correlation between creatinine clearance and enprofylline clearance, while there was only a poor correlation between the liver function tests and theophylline clearance.It appears that in various clinical situations enprofylline elimination can be predicted more precisely than theophylline elimination, which may make the drug safer in clinical practice.     

Pharmacokinetics and bioavailability of reduced and oxidized N-acetylcysteine

Summary The pharmacokinetics and bioavailability of N-acetylcysteine (NAC) have been determined after its intravenous and oral administration to 6 healthy volunteers.According to a randomized cross-over design each subject received NAC 200 mg i.v. and 400 mg p.o., and blood samples were collected for 30 h.Reduced NAC had a volume of distribution (V_SS) of 0.59 l·kg^–1 and a plasma clearance of 0.84 l·h^–1·kg^–1. The terminal half-life after intravenous administration was 1.95 h. The oral bioavailability was 4.0%.Based on total NAC concentration, its volume of distribution (V_SS) was 0.47 l·kg^–1 and its plasma clearance was 0.11 l·h^–1·kg^–1. The terminal half-life was 5.58 h after intravenous administration and 6.25 h after oral administration. Oral bioavailability of total NAC was 9.1%.     

Pharmacokinetics of nicorandil in patients with normal and impaired renal function

Summary The pharmacokinetics of oral nicorandil 20 mg 12 hourly for 9 doses was evaluated in 21 hospitalized patients with angina pectoris due to coronary heart disease and with normal and impaired renal function. Patients were divided into 3 groups based on creatinine clearance (CL_Cr): GROUP I (n=6) > 80 ml/min, GROUP II (n=8) 20–80 ml/min, and GROUP III (n=7) < 20 ml/min.After the first dose, the total clearance of nicorandil (CL) value did not change with increasing renal failure and so was not dependent on creatinine clearance. After the last dose CL was 51 l·h^–1 in Group I, 44 l·h^–1 in Group II and 56 l·h^–1 in Group III, and it was not related to creatinine clearance. The percentage of the dose excreted in the urine was 0.4%. No significant difference was noted in any of the other pharmacokinetic parameters examined in the three groups, not even on comparing values obtained on the first and last days of treatment.The findings suggest that there is no need to change the dose of nicorandil in subjects with different degrees of renal failure.     

Kinetics of intravenous metoclopramide in patients with hepatic cirrhosis

Summary The pharmacokinetics of metoclopramide has been studied after acute IV administration to 12 patients with hepatic cirrhosis (6 with and 6 without ascites) and 6 control subjects.The elimination half-life was significantly longer in patients (11.4 h and 9.9 h in those with and without ascites, respectively, vs 6.4 h in controls). Total plasma clearance was significantly lower in patients (0.29 and 0.36 l·kg^–1·h^–1 vs 0.52 l·kg^–1·h^–1 in controls).The differences between patients with and without ascites did not reach statistical significance. Reduction of functional hepatic blood flow in cirrhotic patients is the probable cause of the observed alteration in metoclopramide kinetics.     

Pharmacokinetics of SUN 1165, a new antiarrhythmic agent,in renal dysfunction

Summary The pharmacokinetics of a new Class I antiarrhythmic agent, SUN 1165, has been studied in 32 patients with varying degrees of renal impairment following a single oral dose of 50 mg.The apparent volume of distribution at steady state was 1.48 1 · kg^–1, the absorption rate constant was 2.2 h^–1, and plasma protein binding was 26.8% in subjects with normal renal function.These variables were not altered with renal impairment. More than 60% of SUN 1165 given orally was excreted unchanged via the kidney, both by tubular secretion and glomerular filtration.The elimination rate constant, the apparent total body clearance and the apparent renal clearance were linearly correlated with the endogenous creatinine clearance. The half-time of elimination was 3.4 h in normal subjects and it was prolonged to 23.7 h in severe renal failure (creatinine clearance below 20 ml · min^–1 · 1.48 m^–2).Dosage adjustment of SUN 1165 is necessary in renal failure.     

Pharmacokinetics of teicoplanin in patients on continuous ambulatory peritoneal dialysis

Summary We have studied the pharmacokinetics of teicoplanin, a new glycopeptide antibiotic active against Gram-positive aerobic and anaerobic bacteria, in five patients with end-stage renal disease on continuous ambulatory peritoneal dialysis (CAPD). Although teicoplanin was eliminated in the peritoneal fluid, relatively little was recovered (6.8±1.2% of the given dose). The following values were obtained: elimination half-time 102–347 h; total body clearance 4.16–7.38 ml·h^–1·kg^–1, peritoneal clearance 0.31–0.37 ml·h^–1·kg^–1. Because the elimination of teicoplanin is about four times less in patients undergoing CAPD compared with subjects with normal renal function, the dose of teicoplanin should be reduced appropriately in such cases.     

Development of a population pharmacokinetic database for tianeptine

Summary Two thousand three hundred and thirty five plasma concentrations of tianeptine from 112 patients enrolled in nine studies of tianeptine pharmacokinetics performed prior to the marketing of the drug were pooled for analysis using mixed-effect modeling. Studies represented a combination of single dose and multiple dosing at steady-state. Tianeptine plasma concentration time data were fit to a two compartment model with first order absorption using the NONMEM computer program.The results of this analysis suggested that alcoholism is associated with significant increase in clearance (124% increase) and volume of the central compartment (161% increase). The volume of the peripheral compartment is significantly lower in women (31% decrease) and in depressed patients (59% decrease).The population mean (interindividual variability) clearance was equal to 0.17 l·h^–1·kg^–1 (28.6%), the volume of central compartment was 0.13 l·kg^–1 (60.4%), intercompartmental clearance was 0.07 l·h^–1·kg^–1 (30.1%), volume of the tissue compartment was 1.17 l·kg^–1 (28.3%), and the absorption rate constant was 0.63 h^–1 (21.8%). The residual variability was approximately 30% at concentrations expected during clinical use of the drug.Because of the increased clearance, alcoholic patients would be expected to have significantly reduced concentrations during steady-state dosing. These population parameters provide a basis for developing initial dosing recommendations and for performing bayesian evaluations of drug concentrations obtained in post-marketing studies.     

Plasma concentrations and haemodynamic effects of nimodipine in patients resuscitated after cardiac arrest

Summary As the pharmacokinetics of a drug may be altered in haemodynamically compromised patients, the plasma concentrations and haemodynamic effects of the calcium entry blocker nimodipine have been examined in patients resuscitated after out-of-hospital cardiac arrest.In 7 patients nimodipine was infused at increasing rates up to 30 µg·kg^–1·h^–1. The plasma concentrations increased with increasing dose; at the highest dose a mean steady-state plasma concentration of 22.1 ng·ml^–1 was obtained, and the mean plasma clearance was 1.4 l·kg^–1·h^–1. There were no marked changes in mean arterial blood pressure or heart rate.In 9 other patients nimodipine was given as a bolus infusion of 10 µg·kg^–1 over 3 min, followed by a continuous infusion of 30 µg·kg^–1·h^–1. A mean steady-state plasma concentration of 17.6 ng·ml^–1 was obtained and the mean plasma clearance was 1.9 l·kg^–1·h^–1. Heart rate did not change significantly, but the mean arterial blood pressure fell.The data indicate that in patients resuscitated after cardiac arrest, the pharmacokinetics of nimodipine are not markedly different from patients with other conditions, e.g. subarachnoid haemorrhage. However, if a loading dose is given to obtain a steady-state concentration sooner, there will be a fall in arterial blood pressure.     

The pharmacokinetics of d-sotalol and d,l-sotalol in healthy volunteers

Summary The pharmacokinetics of d-sotalol has been studied in six healthy volunteers given single doses of 0.25, 0.50, 1, 2 mg·kg^–1 i.v. and one 100 mg oral dose in comparison with the kinetics of 1 mg·kg^–1 i.v. of dlsotalol.There was no significant difference in the disposition of the d-enantiomer and the racemate.The terminal half-life averaged 7.2 h, and the kinetics was linear, with a mean total clearance of 0.13 l·h^–1·kg^–1. Renal clearance of d-sotalol represented 56 to 77% of total clearance. The absolute systemic availability of oral d-sotalol was close to 100% and the elimination half-life of the oral-d-enantiomer was similar to that of the i.v. form (7.5 h).     

Pharmacokinetics and tissue concentrations of ceftazidime in burn patients

Summary The pharmacokinetics and tissue concentrations of ceftazidime have been investigated in 8 patients with severe burns (20–80% of body surface area) undergoing skin transplantation 2 to 21 days after injury. Two prophylactic doses of ceftazidime were administered as 1 g i.v. bolus injections with an 8 h interval. Blood, urine, burn blister fluid and tissue were frequently sampled and drug concentrations were analyzed by HPLC. The kinetics of ceftazidime was the same after each dose.In these patients the pharmacokinetics of ceftazidime was greatly altered from that in other patients and there was much interindividual variation. The mean ceftazidime elimination half-life, apparent volume of distribution and total clearance were: 2.7 h, 30.91 (0.38 l·kg^–1) and 139 ml·min^–1, respectively. A linear correlation was found between creatinine clearance and the renal clearance of the ceftazidime, the mean values being 108 and 95 ml·min^–1, respectively. No correlation was found between creatinine clearance and the total clearance of ceftazidime. The mean percentage urine recovery was 69% of the dose. Tissue and burn blister fluid concentrations were above the MIC, and ranged from 40.0 to 3.1 mg·kg^–1. A substantial increase in the apparent volume of distribution and non-renal clearance of ceftazidime was observed, probably due to increased capillary permeability and drug loss through the wound surface replacement of prior to surgery and subsequently to lost and blood fluid.     

Enprofylline: Pharmacokinetics and comparison with theophylline of acute effects on bronchial reactivity in normal subjects

Summary In a double blind, placebo controlled, crossover study the pharmacokinetics and acute effects of enprofylline and theophylline on airway reactivity during histamine challenge were investigated in 10 healthy volunteers. The pharmacokinetic parameters of enprofylline were (mean): elimination half-life 1.9 h, total body clearance 191.1 ml · kg^–1 · h^–1, volume of distribution 0.48 l · kg^–1, and protein binding 49%. Bronchial reactivity in the histamine inhalation test was expressed as the concentration causing a 20% fall in FEV_1.0 (PC₂₀). Mean PC₂₀ values were lowest after placebo and highest after theophylline with the enprofylline values in between. Only the difference in PC₂₀ ^Safter placebo and theophylline was statistically significant (p<0.05). At the time of determination of the PC₂₀, the serum concentration of enprofylline was between 16.5 and 11.8 µmol/l, and that of theophylline was between 78.3 and 61.1 µmol/l. Adverse actions of enprofylline were nausea (3/10) and cardiovascular reactions (2/10), whereas theophylline mainly caused restlessness (3/10) and tremor (2/10). Thus enprofylline, in one-fifth of the serum concentration of theophylline cannot be regarded as equipotent in terms of bronchoprotection.In fulfillment of his thesis (Dr. med.)     

The influence of steady-state ciprofloxacin on the pharmacokinetics and pharmacodynamics of a single dose of diazepam in healthy volunteers

Summary The effects of pretreatment with a seven day course of ciprofloxacin on pharmacokinetics and pharmacodynamics of an intravenous (5 mg) dose of diazepam were investigated in a group of 12 healthy volunteers in a double-blind placebo-controlled crossover study.Ciprofloxacin pretreatment significantly reduced diazepam CL (without ciprofloxacin: 19.5 ml·h^–1kg^–1; with ciprofloxacin: 12.3 ml·h^–1kg^–1). Diazepam t_1/2 was also prolonged (without ciprofloxacin: 36.7 h; with ciprofloxacin: 71.1 h), but volume of distribution was unaltered (without ciprofloxacin: 1.1 l·kg^–1; with ciprofloxacin: 1.1 l·kg^–1).However, no significant changes were detected in psychometric tests of digit symbol substitution, tapping rate and short memory, as well as levels of concentration, vigilance and tension measured by visual analogue scales.     

Effect of renal insufficiency on the pharmacokinetics of cyclophosphamide and some of its metabolites

Summary Cyclophosphamide pharmacokinetics were studied in seven patients with moderate to severe renal insufficiency (creatinine clearances 0–51 ml · min^–1), and compared with a matched control group of patients with normal renal function. The mean half-life of cyclophosphamide following intravenous administration in the normal group was 8.21±2.33 (SD) h whilst that in renal failure was 10.15±1.80 h: these were significantly different. The total body clearance in the normal control group was 58.6±10.9 ml·kg^–1h^–1 which was significantly larger than in renal failure where it was 48.8±10.9 ml·kg^–1h^–1. V_d , V_{d ss} and V_c were not significantly different between the two groups. A linear relationship exists between , the first order disposition rate constant and endogenous creatinine clearance since this drug shows a relatively small degree of compartmentalisation. The plasma half-life of phosphoramide mustard, a cytotoxic metabolite of cyclophosphamide, shows a parallel and significant increase in renal failure with the parent compound. The t_1/2 in normal patients was 8.33±2.0 h, whilst in the renal failure group it was 13.37±4.23 h. Total alkylating activity as measured by the nitrobenzylpyridine reaction showed a significant increase in renal failure. This data suggests that in pharmacokinetic terms it may not be necessary to alter the dose of cyclophosphamide until there is severe renal impairment. Further studies correlating the efficacy and toxicity of the drug with its pharmacokinetics in renal failure are necessary.     

Pharmacokinetics of cefonicid in children

Summary The pharmacokinetics of cefonicid was studied in 17 children requiring antibiotic treatment for respiratory or urinary tract infections. After informed consent had been obtained from the parents, a single dose of cefonicid 50 mg/kg/body weight was given by intramuscular injection.The mean peak serum concentration of 212.63 µg/ml was reached at 1.00 h, as absorption occurred at a very fast rate with a mean constant of 3.24 h^–1. Mean values for half-life, apparent volume of distribution (V_z), total body clearance (CL), and renal clearance (CL_R) were 3.24 h, 0.21 l·kg^–1, 16.67 ml·min^–1 and 13.60 ml·min^–1 respectively. There was an inverse relationship between age and V_z, whereas CL and CL_R were positively correlated with age. Cefonicid concentrations in urine were many times higher than the MICs of susceptible strains of bacteria.The study demonstrated that i.m. cefonicid 50 mg·kg^–1 gave serum concentrations well within the therapeutic range for susceptible bacteria, and that its pharmacokinetic properties allow single daily doses to be used to treat infections in children.     

Determination of phenobarbitone population clearance values for South African children

Non-linear Mixed Effects Modelling (NONMEM) was used to estimate phenobarbitone population clearance values for South African children, using 52 serum levels gathered from 32 patients during their routine care. NONMEM was also used to evaluate the influence of fixed effects such as weight, age and concomitant medication. The final model describing phenobarbitone clearance was CL=[Exp(0.0288 Wt–2.53)] M, where CL=clearance (l·h^–1), Exp=the base of the natural logarithm, Wt=patient weight (kg) and M=a scaling factor for concomitant medication with a value of 1 for patients on phenobarbitone monotherapy, 0.62 for those receiving concomitant valproate and 0.87 for those patients receiving concomitant carbamazepine or phenytoin. Mean (95% confidence interval) phenobarbitone clearance values were 7.6 ml·h^–1·kg^–1 (6.2, 9.0 ml·h^–1·kg^–1) for the monotherapy group, 5.0 ml·h^–1·kg^–1 (4.0, 6.0 ml·h^–1·kg^–1) in the presence of concomitant valproate and 6.8 ml·h^–1·kg^–1 (5.6, 8.0 ml·h^–1·kg^–1) in the presence of concomitant carbamazepine or phenytoin. These values are similar to those previously reported from both traditional and NONMEM pharmacokinetic studies.     

The pharmacokinetics of cotinine in plasma and saliva from non-smoking healthy volunteers

Summary Cotinine is a major metabolite of nicotine in man. Its disposition kinetics has been followed in plasma and saliva from nine nonsmokers, 23 to 56 years of age. Cotinine 5, 10 and 20 mg was given intravenously and orally to each subject, and plasma, saliva and urine samples were collected for 96 h.The kinetics of cotinine was best described by a multi-compartment model with three distinct phases both in plasma and saliva. Regardless of the mode of administration, there was no indication of dose-dependent kinetics. Mean total plasma clearance was 63.8 ml·h^–1·kg^–1 and mean renal clearance was 4.7 ml·h^–1·kg^–1, i.e. only 10% of the dose was excreted unchanged in the urine. The volume of distribution, as calculated from the plasma curves, was slightly greater than the body weight, 1.1 l·kg^–1. The concentration of cotinine was 20 to 40% higher in unstimulated mixed saliva than in plasma during the absorption, distribution and elimination phases. As the clearance and distribution values in saliva were directly proportional to the corresponding values in plasma, similar terminal half-life values were obtained in the two body fluids, 15.5 and 16.8 h for plasma and saliva, respectively.Thus the kinetics of cotinine is linear after intravenous and after oral dosing, and salivary concentrations give the same information about cotinine disposition in the body as do plasma concentrations.     

Kinetics of morphine in patients with renal failure

Summary The kinetics of morphine and its glucuronidated metabolites were investigated in seven patients with advanced renal failure. The terminal elimination half life of morphine varied between 1.5 and 4.0 h (mean 2.4 h), the volume of distribution between 2.5 and 6.3 l·kg^–1 (mean 4.4 l·kg^–1) and the total plasma clearance between 13.3 and 31.3 l·min^–1·kg^–1 (mean 21.1 l·kg^–1). There were no statistically significant differences between the pharmacokinetic data in the uraemic patients and in a control group of cancer patients with normal kidney function. The concentrations of the glucuronidated metabolites rapidly rose to levels above those of morphine. The elimination half-life of M3G varied between 14.5 and 118.8 h (mean 49.6 h) in the renal failure patients, which is distinctly different from the 2.4 to 6.7 h (mean 4.0 h) found in patients with normal kidney function. There was a significant correlation between the half-life of M3G and renal function estimated as serum urea. Thus, the metabolism of morphine in patients with kidney disease is not significantly impaired. The clinical importance of the high concentrations of glucuronides in uraemic patients is not known.     

Pharmacokinetics of ciprofloxacin tablets in renal failure; influence of haemodialysis

Summary The pharmacokinetics of ciprofloxacin has been studied after a single oral dose of 500 mg given to 5 normal subjects (N) and to 15 patients grouped according to their residual renal creatinine clearance: Group I, 8–30 ml·min^–1, Group II, <8 ml·min^–1, and Group III, haemodialysed patients studied twice — during an interdialysis period (IIIa) and in a 4 h haemodialysis session (IIIb). Ciprofloxacin was assayed by reverse phase HPLC using a spectrofluorimetric detection. The peak plasma concentration (2–5 mg·l^–1) was reached within 2 h after drug administration. Apparent volume of distribution, 6.6 (N), 5.0 (I), 2.7 (II) and 4.2 (IIIa) l·kg^–1 and total plasma clearance, 770 (N), 440 (I), 378 (II) and 314 (IIIa) ml·min^–1 were decreased in relation to the degree of renal impairment. Mean plasma half-lives for patients in the 4 groups were 7.3 (N), 10.4 (I), 7.2 (II) and 9.3 (IIIa) h. In groups N, I and II, 40, 16 and 8% of the administered dose was eliminated through the kidney, with mean renal clearances of 305±63,61±21 and 21±3 ml·min^–1. A linear relationship was found between the renal clearance of ciprofloxacin and the glomerular filtration rate (r=0.75,n=15). Ciprofloxacin was partly removed by haemodialysis (IIIb): the dialyser extraction ratio was 23% and the dialysis clearance was 40 ml·min^–1.     

Pharmacokinetics of intravenous omeprazole in children

This study was undertaken to define the pharmacokinetics of omeprazole in children and included 13 patients, heterogenous in terms of age (0.3 to 19 years), underlying disease and biological constants, indication of omeprazole administration and associated therapy. The dose administered ranged from 36.9 to 139 mg·1.73 m^–2.The pharmacokinetic parameters of omeprazole were: systemic clearance, 0.23 1·kg^–1·h^–1; volume of distribution, 0.45 1·kg^–1; elimination half life 0.86 h; but were highly variable between individuals. Dosage, differences in hepatic and renal function and associated therapy may contribute to inter-individual variability.Within the range of doses administered, the pharmacokinetic parameters were similar to those reported in adults. The drug has been well tolerated in all children.     

Pharmacokinetics of ethanol in plasma and whole blood: estimation of total body water by the dilution principle

Summary The pharmacokinetics of ethanol in plasma and whole blood have been investigated and the results used to estimate the volume of total body water (TBW) by means of the dilution principle. Fifteen men (mean age 62 y) were given 0.6 g ethanol/kg body weight as an intravenous infusion over 1 h.The peak concentration of ethanol in plasma was 120 mg·dl^–1 compared to 108 mg·dl^–1 for whole blood. The disappearance rate of ethanol from plasma was 18.6 mg·dl^–1·h^–1 compared to 17.0 mg·dl^–1·h^–1 for the whole blood concentration-time data. The apparent volume of distribution of ethanol (V_z) was 0.54 l·kg^–1 according to plasma kinetics compared to 0.59 l·kg^–1 for the kinetics derived from whole blood. The mean area under the curve (AUC) was 294 mg·dl^–1×h for plasma kinetics compared to 266 mg·dl^–1×h for whole blood. The TBW was 40.9 l or 50.9% of body weight for the plasma concentration-time data. This agreed well with the 40.3 l or 50.1% of body weight obtained using whole blood.