Excretion of hydroflumethiazide in bile and urine of man

Summary Biliary and urinary excretion of hydroflumethiazide (HFT) and its metabolite, 2,4-disulfamyl-5-trifluoromethylaniline (DTA), was investigated in 5 otherwise healthy patients with a T-drain in the common bile duct after cholecystectomy and choledochotomy. After a single oral dose of HFT 302–453 µmoles, a mean of 0.051% (range 0.028–0.075) of the dose was excreted in bile and 34.9% (range 23.7–45.4) in urine during the first 6 hours after administration. Biliary excretion appeared to be of minor importance in the elimination of HFT by man. DTA could not be detected in bile.     

Distribution and elimination kinetics of carbamazepine in man

Summary Carbamazepine (2.7–3 mg/kg) was administered orally as an alcoholic solution (50% v/v) to eight healthy volunteers. Two of the subjects were also given 50 mg and 100 mg of carbamazepine in alcoholic solution and 200 mg as a tablet. Plasma concentrations, which were analysed by mass fragmentography, reached a maximum 1 – 7 hours after dosing, and then declined monoexponentially with half-lives ranging from 24 to 46 hours. The half-lives were independent of dose. The apparent distribution volume ranged from 0.79 to 1.40 l/kg. It was found that 72% of carbamazepine was bound to plasma proteins with little interindividual variation, and this was not influenced by the presence of diphenylhydantoin or phenobarbital in therapeutic concentrations. The pharmacokinetic parameters calculated from single oral doses were used to predict the steady-state plasma concentration expected after treatment with multiple doses of 200 mg three times daily. The predicted steady-state concentration was 2 – 3 times higher than that reported in patients undergoing chronic treatment with carbamazepine at this dose level, i.e. the pharmacokinetics of carbamazepine apparently change during multiple dosing.Dedicated to the memory of Balzar Alexandersson, MD.Medical Research Council (U.K.) Travelling Fellow     

Pharmacokinetics of hydroflumethiazide during repeated oral administration to healthy subjects

Summary The pharmacokinetics of hydroflumethiazide (HFT) were investigated during repeated oral administration of 100 mg (302 µmoles), every 24 h for 7 consecutive days, to 6 healthy male volunteers. HFT and a metabolite, 2,4-disulfamyl-5-trifluoromethylaniline (DTA), were determined by TLC and spectrofluorodensitometry. Steady state had been reached on the fourth day (judged by urinary excretion rates of HFT and DTA). The mean biological half-life of HFT was 6.85 h (range 5.1–8.7), and the mean half-life of DTA was 17.7 h (range 11.1–21.0). The accumulation factors (expressed as relative increase in urinary excretion rates 12–24 h after doses) were 1.15 for HFT and 2.28 for DTA, which is in reasonable agreement with what can be predicted from the half-lives. The mean fraction of the dose excreted in urine as HFT was 0.652 (range 0.53–0.73) and as DTA 0.049 (range 0.035–0.073), during one dosage interval at steady state. The mean renal plasma clearance of HFT was 0.3561 · h^–1 · kg^–1 (range 0.310–0.402), and the mean instant volume of distribution of HFT was 3.491 · kg^–1 (range 2.78–4.76). DTA was not detected in plasma, but reached a concentration in the red cell fraction which was higher than that of HFT during most of the dosage interval. DTA was therefore excreted in urine with a longer apparent t_1/2 and it accumulated to a greater degree than the parent drug.     

Pharmacokinetics of hexobarbital in man after intravenous infusion

The plasma levels of hexobarbital in humans were determined during and after a 30-min or 60-min zero-order intravenous infusion. Hexobarbital kinetics could be described by conceiving the body to exhibit two compartments. The plasma concentrations were fitted to the postinfusion equation and the parameters intrinsic to the two- compartment open model were estimated. The elimination half-life varied considerably among the 14 individuals (160–441 min), which could mainly be explained by the greatly varying metabolic clearance of the compound (123–360 ml /min). The apparent volume of distribution per kilogram of body weight was relatively constant (1.10±0.12 liters/kg).This work was supported in part by a grant from the Netherlands Foundation for Medical Research FUNGO.     

Pharmacokinetics of propylthiouracil in man after intravenous infusion

The kinetics of propylthiouracil in man was evaluated in four subjects after intravenous infusion at different infusion rates. Significant correlation among the rate of infusion, steadystate plasma levels, and AUC sustained the assumption of a doseindependent kinetics. The total body clearance and the elimination halflife evaluated after cessation of the infusion were in close agreement with values obtained in a previous study after intravenous bolus injection. The total volume of distribution was larger after infusion than found in the singleinjection studies. Data obtained from the infusions made it possible to evaluate the a phase indirectly.This work was supported by Grant 512-4121 from the Danish Medical Research Council, Copenhagen.     

Dose-dependent absorption and elimination of cefadroxil in man

Summary The pharmacokinetic behaviour of cefadroxil was dose-dependent in healthy male volunteers following the oral administration of single doses of 5, 15, and 30 mg · kg^–1.As the dose of cefadroxil increased from 5 to 15 and 30 mg · kg^–1, the peak plasma concentrations, normalized to 5 mg · kg^–1, decreased significantly from 15.1 to 10.7 and 7.6 mg·l^–1, while the corresponding normalized areas under the plasma concentration-time curves from 0 to 2 h decreased significantly from 1258 to 946 and 801 min·mg·l^–1.When the same subjects were given 5 mg·kg^–1 of cefadroxil together with 45 mg·kg^–1 of cephalexin, the absorption of cefadroxil was slowed to a similar or greater extent than with the high dose of cefadroxil.Although the absorption rate decreased as the dose increased, the systemic availability of cefadroxil was essentially complete at all doses, as judged by the 24 h urinary recoveries of the antibiotic. Kinetic analysis of the plasma concentration-time curves gave the best fit with a zero-order followed by a first-order absorption process, consistent with saturable intestinal absorption of cefadroxil.The elimination rate of cefadroxil was directly related to dose and plasma concentrations, and the clearance at the dose of 5 mg·kg^–1 was significantly increased by the simultaneous administration of high-dose cephalexin.The renal clearance of cefadroxil ranged from 98 ml·min·l^–1 at total plasma cephalosporin (cefadroxil + cephalexin) concentrations less than 2.5 mg·l^–1 to 156 mg·l^–1 at concentrations greater than 40 mg·l^–1. These findings are consistent with saturable active gastrointestinal absorption and renal tubular reabsorption of cefadroxil, with competitive inhibition of both processes by cephalexin.     

Hepatic enzyme induction and vitamin K1 elimination in man

Summary We have studied the single dose and steady-state pharmacokinetic of tiaprofenic acid in ten elderly arthritic patients living in the community (5 men and 5 women) taking 200 mg tid for 8 days.The mean area under the plasma concentration-time curves to 8 h (AUC (0–8)) did not alter significantly from day 1 to day 8 (77.25 to 79.61 µg·ml^–1. h). The mean terminal phase half-life (t_1/2) was 2.05 h and 2.25 h on Days 1 and 8 respectively in patients in whom the calculations were possible (7 patients on Day 1 and 6 patients on Day 8). The median observed time of maximum concentration (t_max) and the mean observed maximum plasma concentration (C_max) of 100 min and 21.3 µg·ml^–1 respectively on Day 1 were not significantly different from the values obtained on Day 8 (t_max 120 min; C_max 20.7 µg·ml^–1). The kinetic data suggest that there should be no significant accumulation of tiaprofenic acid in elderly ambulant people suffering from arthritis.     

Distribution and elimination of digoxin in infants

Summary The distribution and elimination of intravenous digoxin were investigated in seven neonates and infants with heart failure. Serum digoxin concentrations during a 24 h period were determined by radioimmunoassay, using¹²⁵I as tracer. The serum values declined biexponentially after the injection and could be fitted to a two-compartment open model by non-linear least-squares regression. The calculated mean half-lives of the distribution (alpha) phase in neonates and infants were 37 and 28 min, respectively. The mean half-life of the elimination (beta) phase in neonates was 44 h, as compared to 19 h in infants. The mean volume of the central compartment and the mean volume of distribution at steady-state were calculated to be 1.3 and 9.9 l/kg, respectively; no significant differences between neonates and infants were found. The relation between these volumes indicates that digoxin is extensively distributed in tissues. The steady-state distribution volumes of digoxin in neonates and infants exceed those reported in adults. The larger volume of distribution might explain in part why infants with cardiac insufficiency require larger doses of digoxin than adults (on a mg/kg body weight basis) to obtain the same serum concentrations. Elimination of digoxin from the body was slower in neonates than in infants.     

The disposition of intravenous doxapram in man

Summary The pharmacokinetics of intravenous doxapram in healthy individuals is consistent with a three-compartment open model. Doxapram was administered by bolus injection (1.5 mg · kg^–1) and by intravenous infusion (6.5 mg · kg^–1 for 2 h) to 5 subjects on separate occasions. There was no significant difference in mean terminal plasma half-lives (355 and 448 min) or in mean total body clearances (5.9 and 5.6 ml · min^–1 · kg^–1) following i. v. bolus injection or infusion respectively. In 3 subjects plasma doxapram concentrations during and after i. v. infusion agreed with those predicted from pharmacokinetic values obtained from the bolus injection study. Since mean steady-state concentrations (9.9 µg · ml^–1) would be reached only after an extended interval (mean 15.2 h), a variable-rate infusion regimen was calculated to produce and maintain a concentration of 2 µg · ml^–1 from 15–25 min onwards. A regimen in which the infusion rate is reduced step-wise is recommended to achieve early near-constant plasma doxapram concentrations.     

Pharmacokinetics of amitriptyline infused intravenously in man

Summary Amitriptyline was given to four male volunteers by constant rate intravenous infusion. Blood samples were collected before, during and at various times after the infusion for estimation of the serum concentrations of amitriptyline. The level of nortriptyline never reached a detectable level. A two compartment open model was shown to be applicable to the data obtained. The meaning of the parameters obtained by a non-linear, least squares curve fitting procedure is discussed and the values are compared to those recently published for nortriptyline. The calculated biological half-life of amitriptyline was about 17 hours, a figure which differs considerably from previously calculated values for volunteers, but is in accordance with some newer results from patients.     

Pharmacokinetics of fenbufen in man

Summary The pharmacokinetics of fenbufen (3.4-biphenylylcarbonyl propionic acid) a new antiinflammatory agent, and its metabolites, -hydroxy-4-biphenylbutyric acid and 4-biphenylacetic acid have been studied after oral administration to seven patients with rheumatoid arthritis. Fenbufen was administered as a single oral dose of 600 mg in hard gelatine capsules. A specific, sensitive gas chromatographic method was used to measure the concentration of the three compounds. A linear two-compartment open model appeared suitable to describe the course of the plasma level of fenbufen with time. This compound appeared in the blood after a lag time of 0.45 h and the peak plasma concentration of 5.97 µg/ml was observed after 1.19 h. The half-life of plasma disappearance was 10.26 h for fenbufen and 10.07 h and at 9.95 h for metabolites II and III, respectively.     

Rapid and slow benzbromarone elimination phenotypes in man: benzbromarone and metabolite profiles

Summary Following oral administration of the uricosuric drug benzbromarone two major metabolites appear in the circulation, 1'-hydroxy-benzbromarone (M1), and a second product (M2) of unknown structure. The plasma concentrations of the parent drug and of M1 and M2 have now been compared in two different elimination phenotypes, 10 subjects who eliminated the drug rapidly (S1–10) and one individual (S11) whose elimination capacity was impaired, presumably due to genetic variation (S11). The AUC (0–96) of the parent drug in S11 was 145 gmg · ml^–1 h, and in the other individuals it averaged 18.3 (11.4–24.5) g · ml^–1 h. The plasma elimination half life of benzbromarone was 3.34 (1.77–5.24) h in the rapid eliminators, and 13.08 h in the subject with the elimination defect. The mean plasma elimination half life of the metabolites in S1–10 amounted to 20.1 (11.9–41.2) h for M1, and 17.2 (12.9–30.7) h for M2. In S11 the plasma elimination half life of M1 was prolonged to 76.6 h, and of M2 to 75.4 h. Thus, the elimination defect in S11 was not restricted to the parent drug, but it also involved the two major metabolites M1 and M2. This might be a consequence of a hepatic enzyme deficiency, or be due to impairment of drug excretion.     

Pharmacokinetic consequences and toxicologic implications of metyrapone-induced alterations of acetaminophen elimination in man

Summary This study examined the effect of metyrapone on the elimination rate of acetaminophen and on the apparent formation rate of acetaminophen metabolites in man.Metyrapone treatment, 1.5 g, increased the half-life of acetaminophen, decreased the fraction of the dose recovered in the urine as the glucuronide and increased the fraction of the dose recovered in urine as the sulfate and mercapturate conjugates. The apparent rate constant for the formation of acetaminophen glucuronide was significantly decreased by metyrapone while the apparent rate constants for the formation of the sulfate and mercapturic acid metabolites were unchanged or slightly increased, respectively.These data indicate that metyrapone inhibits acetaminophen glucuronidation and possibly enhances the oxidation of acetaminophen to its quantitatively minor yet highly toxic reactive metabolite. The extent to which the parallel pathways of acetaminophen elimination are also affected by inhibitors of cytochrome P-450-mediated oxidation will limit the efficacy of these types of potential antidotes for the treatment of acetaminophen overdose.     

Pharmacokinetics of mefruside and two active metabolites in man

Summary Single oral doses of mefruside 25 or 50 mg were administered to eight healthy human subjects and plasma, red blood cells and urine were assayed for up to 50 h. In four of the subjects, the concentrations of two active metabolites of mefruside, 5-oxomefruside (mefruside-lactone) and its hydroxy carboxylic acid analogue, were also measured. Mefruside was rapidly absorbed into plasma, with a mean half-life of 0.5 h. A 4-fold interindividual difference in elimination half-life was observed, ranging from 2.9–12.5 h. The decay was biphasic in five of the eight subjects. In the other three, who had the shortest t_1/2 values, initial distribution was not visible as a separate phase, so monophasic decay resulted. The variation in t_1/2 was reflected in large differences in total plasma clearance between subjects (22.5–129 l/h). The total volume of distribution ranged from 314–518 l. Mefruside distributed instantaneously between plasma and red cells. The concentration in red cells was about 30 times higher than in plasma, and the terminal decay was parallel to that in plasma. The urinary excretion rate of mefruside also paralleled the plasma concentration curve. A mean total of 0.49% (±0.30%, SD) of the dose was excreted as the unchanged compound in urine over infinite time. Measurable concentrations of 5-oxomefruside were observed in the red cell fraction in the first samples, i. e., at 0.5 h. The carboxylic acid metabolite reached red blood cell concentrations about 10 times lower than those of 5-oxo-mefruside. The plasma concentrations of these metabolites were too low to be measured, but high concentrations were found in urine. Total urinary excretion of the lactone metabolite over infinite time ranged from 12.0–14.5% of dose (mean ± SD, 13.1±1.1%), and that of the open acid metabolite was 34.6–54.2% of dose (mean ± SD, 46.2±9.6%). A further 5–15% of the dose was recovered from urine after enzymatic hydrolysis as a conjugate of the open acid metabolite. The urinary excretion rate of the two main metabolites became maximal between 5–10 h after administration of mefruside, and the subsequent decrease showed much less intersubject variation in t_1/2 than that observed for the parent compound. A mean t_1/2 of 11.9 (±1.7 h, SD) was measured for the lactone, and a mean t_1/2 of 10.5 h (±1.6 h, SD) for the acid metabolite. Approximately the same t_1/2 resulted from red cell measurements. It was concluded that the urinary excretion profile of both metabolites corresponded very well to the known duration of clinical action of mefruside, so that the metabolites instead of the parent drug must be considered as the actual therapeutic principle in man.     

Fluorometric determination of hydroflumethiazide in human plasma and urine after its oral administration

Summary A spectrofluorometric method for determination of hydroflumethiazide in human plasma and urine has been developed. The limit of detection was 10 ng/ml plasma and 100 ng/ml urine. The plasma concentration of hydroflumethiazide was determined for 9–11 hours and excretion in urine for 24–37 hrs after oral administration of about 1 mg/kg body weight to 7 subjects. Plasma half life in healthy subjects was 1.9–2.1 h, and 2.7–8.6 h in patients during the period 4–9 hrs after dosing. Cumulative excretion in urine was 67–79% of the dose during 31–37 hrs in 6 subjects; one patient with renal disease was found to excrete only 25.8% of dose during 24 hours. Renal clearance of hydroflumethiazide was higher in the healthy subjects (0.29–0.44 1 h^–1 kg^–1) than in the patients (0.040–0.15 l h^–1 kg^–1). Plasma half life of hydroflumethiazide was not closely correlated with renal clearance of the drug, which suggests that other factors may play a role in determining plasma half life.     

Distribution and elimination kinetics of intravenously and intramusculary administered tobramycin in man.

The pharmacokinetic profile of Tobramycin, a new aminoglycoside antibiotic, has been determined in man following intravenous and intramuscular administration. The serum elimination of the antibiotic obeys two-compartment open model kinetics after intravenous injection. The fast (alpha) and slow (beta) disposition rate constants averaged 0.1169 min-1 and 0.0099 min-1 respectively. The volume of distribution at the steady-state averaged 0.123 liter kg-1 and the plasma clearance 0.8 ml min-1 kg-1. Calculation of the intrinsic absorption rate of an intramuscular dose according to the two-compartment open model indicates that absorption increases during the first 40 minutes, then decreases and is virtually complete 90 minutes after administration in all subjects. The absolute physiological availability of the intramuscular dose averaged 84.9%. A method of administration compatible with the kinetic properties of the drug is proposed.     

Pharmacokinetics of a single oral dose of hydroflumethiazide in health and in cardiac failure

Summary The pharmacokinetics of hydroflumethiazide (HFT) were investigated after single oral doses of 6 µmoles/ per kg body weight in five healthy subjects and in nine patients with moderate cardiac failure. HFT was excreted in urine together with 2,4-disulfamyl-5-trifluoromethylaniline (DTA), which was also present in the blood after administration of HFT. HFT and DTA were determined by TLC and spectrofluorodensitometry. Mean cumulative urinary excretion of HFT was 46.5 and 47.5 per cent of the dose both in healthy subjects and in patients. Distribution half-life (t1/2) was about 2 h in both groups of subjects, while biological half-life (t1/2) ranged from 12.4 to 26.9 h (mean 16.6) in healthy subjects, and from 6.3 to 13.7 h (mean 9.6) in patients. Mean renal clearance was 0.33 and 0.211 · h^–1 · kg^–1 in normal subjects and patients, respectively, and was almost equal to the total body clearance. HFT had a large apparent volume of distribution (V), with mean values of 6.4 and 3.11 · kg^–1 in normal subjects and patients. Mean cumulative urinary excretion of DTA was 1.8 and 1.9 per cent in healthy subjects and patients with cardiac failure. The apparent half-life of DTA, determined from urinary excretion rate in eleven subjects, ranged from 16 to 56 h but half-lives in three others were more than 100 h. The results indicate that HFT is partly metabolized in the body to DTA, and DTA and HFT are excreted in urine. The half-life of DTA was longer than that of the parent drug. The apparent volume of distribution, clearance and biological half-life of HFT were lower in patients with cardiac failure than in healthy subjects.     

Distribution of lithium elimination rates in a selected population of psychiatric patients

Summary Chronic treatment with conventional lithium carbonate was interrupted in a selected group of 40 psychiatric patients of mixed sex and race. All patients had normal renal function. Serum samples were taken 12, 24, 36 and 48 h after the last dose and lithium was assayed by atomic absorption spectrophotometry. Decay rates calculated for the 12–24 h and 36–48 h periods yielded different values. This was ascribed to the presence of an incomplete redistribution phase during the earlier period. The distribution of elimination rates determined during the later period gave a more symmetrical spread and approximated a normal distribution. The mode, median, mean and standard deviation of the lithium elimination half-lives were 12.5, 14, 18.2 and 7.3 h and 22.5, 24.5, 29.8 and 10.1 h for the two periods, respectively. The results contrast sharply with another report of the distribution spread of elimination half-lives in a much larger sample. The current values have implications for dosage prediction, serum level monitoring and dosage formulation, especially sustained-release preparations. The evidence was against the possibility that some individuals retain lithium.     

Distribution,elimination and natriuretic effect of furosemide in patients with severe arterial hypertension

Summary Furosemide 40 mg was injected intravenously in 7 patients with severe hypertension and vascular complications. A two compartment, open model was used to describe the disappearance of the drug from serum. The mean serum clearance (Cl_s=1.83 ml/min · kg) was significantly reduced compared to the mean Cl_s-value of a group of normals (2.96 ml/min · kg). A significant correlation was found between Cl_s and mean blood pressure, as well as between Cl_s and renal clearance (mean Cl_r=0.83 ml/min · kg); extrapolation of the regression line yielded a Cl_s-value of 50 ml/min for Cl_r=0. The Cl_r was also significantly negatively correlated with mean blood pressure. Protein binding of furosemide was normal, except in one patient, who had considerable impairment of renal function. Apparently more than 90% of unchanged furosemide passed in urine was excreted by tubular transport. A highly significant negative correlation was found between Cl_s and the fraction of furosemide excreted as a glucuronide. During the first two hours, significantly less sodium was excreted by the patients than by a comparable group of normal subjects. The correlation between serum concentration of furosemide and the amount excreted of sodium was not significant, but highly significant correlations were found between the amounts of furosemide and sodium excreted by the kidney in 0–30 and 0–60 min. In all the individual patients an approximately linear relationship with wide variation in the slope was found between the cumulative excretion of furosemide and sodium from 0–30 min to 0–60 and to 0–120 min. After 120 min deviations were observed in the curves from 4 of the patients, which indicated that smaller and smaller additional amounts of sodium were excreted with constant additional amounts of furosemide.     

The elimination of phenytoin in man

1. Plasma phenytoin (diphenylhydantoin) levels after different drug doses were correlated with urinary 5-(p-hydroxyphenyl)-5-phenylhydantoin (p-HPPH) excretions in four subjects. 2. In three of four subjects the proportion of the phenytoin dose that was excreted as p-HPPH diminished as the dose increased. In the fourth, p-HPPH output remained proportionate to dose of phenytoin until elimination of the drug fell below its input. 3. Plasma p-HPPH levels were measured in two subjects; the data suggested that the renal excretion of p-HPPH was not rate-limited. 4. In three of four subjects, there was the possibility that alternative pathways for eliminating phenytoin may have developed as drug doses increased and the capacity for forming p-HPPH became saturated. 5. Overall phenytoin elimination appeared to approach saturation at concentrations of the drug encountered therapeutically. When Michaelis-Menten kinetics were applied to data for phenytoin elimination in twenty-one adults and fifteen children, the mean apparent K_m value for the adults corresponded to a plasma drug concentration of 5·8 μg/ml, and in the children to 5·3 μg/ml. The mean V_max values in the two groups were, respectively 8·1 mg/kg per day and 12·5 mg/kg per day.