Plasma kinetics and urinary elimination of saccharin in man

The plasma kinetics and urinary elimination of saccharin were studied in 3 groups each of 5 healthy male volunteers given the sweetener as three different single oral doses (50, 150 and 333 $\text{mg}\text{60 kg}$ body weight). Saccharin concentrations were determined by gas liquid chromatography-stable isotope dilution mass fragmentography.The compound was rapidly absorbed through the gastrointestinal tract, reaching plasma peak concentrations between 30 and 60 min after intake. Plasma saccharin elimination was also fast, with a monoexponential pattern of decay. At the 3 doses studied saccharin was excreted in urine within a few hours, about 60% of the dose being excreted unchanged at 6 h and 76% at 24 h.     

Plasma kinetics of methaqualone in man after single oral doses

Summary Plasma concentrations of methaqualone were followed for several days after single oral doses in 5 healthy subjects. The analysis of methaqualone was performed by gas chromatography-mass spectrometry (mass fragmentography). The plasma levels of methaqualone were interpreted according to a two compartment model. The elimination rate of methaqualone was found to be much slower than has been reported previously, half lives in the -phase ranging from 19.6 to 41.5 h.     

Plasma kinetics and urinary excretion of primaquine in man.

1 The kinetics of primaquine have been studied in twenty volunteers after single and multiple dose regimes. 2 The kinetic parameters were similar in glucose-6-phosphate dehydrogenase (G6PD) normal Thais, G6PD deficient Thais and in Caucasians. 3 The Caucasian subjects showed about 1% of the dose was excreted in the urine. 4 The kinetic parameters obtained from multiple dose studies in Thais were very similar to those obtained from single dose studies in Thais.     

Effect of DDAVP on plasma renin activity in man.

We have investigated in eight healthy persons the effect of a single intranasal dose of 40 microgram DDAVP on plasma renin activity (PRA) in the upright posture. During normal sodium intake there were no differences in the PRA values between the time-control and DDAVP studies. However, during sodium restriction in four subjects with higher initial PRA, DDAVP induced a 40% decrease, lasting no longer than 45 minutes. There was no change in PRA after DDAVP in the other four subjects with much lower initial levels. Although no major or consistent suppressive influence could be demonstrated in the present study, in certain persons with highly stimulated initial PRA levels a transitory slight depression may be expected after a pharmacological dose of DDAVP.     

Plasma kinetics of carbamazepine and its epoxide metabolite in man after single and multiple doses

Summary Carbamazepine (Tegretol^®) was administered orally to four patients as a single dose, and one week later three times daily for 15–21 days. The plasma half-lives of the drug were shorter in all patients after multiple doses (20.9±5.0 hours) than after the initial single dose (35.6±15.3 hours). During multiple doses the plasma concentrations of the metabolite carbamazepine-10,11-epoxide followed those of the parent drug. The steady-state plasma concentrations expected during multiple doses were calculated from the pharmacokinetic parameters obtained in the single dose studies. The calculated levels were higher (17.2±7.2 µg/ml) than the observed maximal concentrations (8.4±1.6 µg/ml on day 4), which were obtained 3–4 days after starting the multiple doses. The levels tended to decrease further during the experimental period. The results suggest that carbamazepine induces its own metabolism in man.     

Disposition kinetics of ethambutol in man

Six normal adult volunteers were administered 15 mg/kg of ethambutol (EMB) by a constant-rate 1-hr infusion. Plasma and urine samples were collected up to 24 and 72 hr, respectively. Peak plasma levels following the 1-hr infusion ranged from 11.6 to 15.4 g/ml. Subsequent postinfusion EMB levels exhibited multiphasic decay. In the 12-hr period following infusion, EMB levels showed biexponential decay. However, 24-hr plasma levels in all subjects were observed to be higher than those predicted using a two-compartment body model. The phase in these subjects had a mean half-life of 8.6 min while the half-life of the phase ranged from 2.5 to 3.6 hr (mean 3.1). The half-life of the phase estimated from plasma data points between 12 and 24 hr averaged 11.2±3.6 hr. A terminal t_1/2 of 15.4±1.7 hr was calculated from 12–72 hr urine data. The mean value for the steady-state volume of distribution using a noncompartmental method was 3.89 liters/kg. Plasma EMB clearance ranged from 7.47 to 9.87 ml/min/kg (mean 8.57). The fraction of the dose eliminated unchanged varied from 0.75 to 0.84 (mean 0.79). Renal clearance ranged from 5.93 to 8.45 ml/min/kg (mean 6.81), indicating active tubular secretion.This work was supported in part by NIH Grant GM 26551.     

Dose-dependent kinetics of ethotoin in man

• 1 A gas-chromatographic assay for the anticonvulsant drug ethotoin in plasma has been used to establish a kinetic basis for therapy in eight newly diagnosed epileptic patients.
• 2 Only a small fraction of ethotoin was excreted unchanged. Elimination curves were only rectilinear below a plasma concentration of 8 mg/l. During constant medication plasma concentrations tended to decrease in the first week. Steady-state plasma levels varied considerably between individuals. For all patients the plasma concentration/dose ratio increased with increasing dose.
• 3 Most of the results point to dose-dependent elimination kinetics in the therapeutic range and parallel what is known for phenytoin. Control of therapy by measurement of plasma levels of ethotoin is accordingly advocated.

     

Dose-dependent kinetics of inhaled methylethylketone in man

Physiologically based stimulation of earlier human inhalation exposure to methylethylketone (MEK) at a concentration of 200 ppm for 4 h suggested that the kinetics were dose-dependent. Two male volunteers were therefore exposed to MEK for 4 h at 3 exposure concentrations: 25, 200 and 400 ppm. Blood MEK concentrations were monitored during and after exposure. The results showed clearly that the kinetics of MEK were dose-dependent at higher exposure concentrations. Simulated exposure to MEK for 8 h suggests that saturation kinetics are reached at an exposure concentration of 50–100 ppm, depending on the physical work load.     

Metabolism and kinetics of amlodipine in man

1. The disposition of amlodipine, R,S,2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl- 5- methoxycarbonyl-6-methyl-1,4-dihydropyridine has been studied in two human volunteers using single oral and intravenous doses of 14C-amlodipine. The drug was well absorbed by the oral route while the mean oral bioavailability for unchanged drug was 62.5%. 2. Renal elimination was the major route of excretion with about 60% of the dosed radioactivity recovered in urine. Mean total recovered radioactivity in urine and faeces amounted to 84% for both the oral and intravenous routes. 3. Apart from a small amount of unchanged amlodipine (10% of urine 14C), only pyridine metabolites of amlodipine were excreted in urine. The majority (greater than 95%) of the metabolites excreted in the 0-72 h post-dose period were identified; the major metabolite was 2-([4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl- 2-pyridyl]methoxy) acetic acid and this represented 33% of urinary radioactivity. The data indicate that oxidation of amlodipine to its pyridine analogue is the principal route of metabolism with subsequent metabolism by oxidative deamination, de-esterification and aliphatic hydroxylation. 4. For the two volunteers, amlodipine concentrations in plasma declined with a mean half-life of 33 h, while slower elimination of total drug-related material from plasma was observed, consistent with prolonged excretion (up to 12 days) of metabolites in urine and faeces. Only amlodipine and pyridine metabolites were found in the circulation. As these pyridine derivatives have minimal calcium antagonist activity the efficacy of amlodipine in man can most probably be attributed to the parent drug.     

Metabolism and kinetics of amlodipine in man

1. The disposition of amlodipine, R,S,2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine has been studied in two human volunteers using single oral and intravenous doses of ¹⁴C-amlodipine. The drug was well absorbed by the oral route while the mean oral bioavailability for unchanged drug was 62˙5%.

2. Renal elimination was the major route of excretion with about 60% of the dosed radioactivity recovered in urine. Mean total recovered radioactivity in urine and faeces amounted to 84% for both the oral and intravenous routes.

3. Apart from a small amount of unchanged amlodipine (10% of urine ¹⁴C), only pyridine metabolites of amlodipine were excreted in urine. The majority (<95%) of the metabolites excreted in the 0-72h post-dose period were identified; the major metabolite was 2-([4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-2-pyridyl]methoxy) acetic acid and this represented 33% of urinary radioactivity. The data indicate that oxidation of amlodipine to its pyridine analogue is the principal route of metabolism with subsequent metabolism by oxidative deamination, de-esterification and aliphatic hydroxylation.

4. For the two volunteers, amlodipine concentrations in plasma declined with a mean half-life of 33 h, while slower elimination of total drug-related material from plasma was observed, consistent with prolonged excretion (up to 12 days) of metabolites in urine and faeces. Only amlodipine and pyridine metabolites were found in the circulation. As these pyridine derivatives have minimal calcium antagonist activity the efficacy of amlodipine in man can most probably be attributed to the parent drug.     

Divided-dose kinetics of mefloquine in man.

The kinetics of mefloquine was investigated following oral divided-doses in 10 healthy Caucasian volunteers. They received 500 or 750 mg followed by 500 mg 8 h later. Unchanged mefloquine (M) and its carboxylic acid metabolite (MM) were measured in whole blood and plasma for 50 days by h.p.l.c. Maximum blood and plasma M concentrations of 1872 +/- 362 ng ml-1 (mean +/- s.d.) and 1900 +/- 434 ng ml-1, respectively, were found within 6-10 h after the second dose. The terminal plasma elimination half-life was 20.1 +/- 3.7 days (mean +/- s.d.) and the oral clearance was 22.3 +/- 6.7 ml h-1 kg-1 (mean +/- s.d.). Plasma concentrations of MM exceeded those of M by 2-3 fold within 2 days. The whole blood concentration of MM was lower than that in plasma but also exceeded the whole blood concentration of M.     

Effects of probenecid on enprofylline kinetics in man

Summary Enprofylline 1 mg/kg, a new potent antiasthmatic xanthine derivative, which is mainly eliminated by renal excretion, was given intravenously to 6 normal subjects with and without oral pretreatment with 1 g probenecid. The latter caused a drop in the average total body clearance of enprofylline from 21 to 9.8 l/h, and in the average renal clearance from 17 to 8.0 l/h. The average half-life increased from 1.8 to 3.0 h. The volumes of distribution, V_z and V_ss, both fell by about 25%, indicating that probenecid had restricted the distribution of enprofylline in the body. The plasma protein binding of enprofylline was not altered by probenecid. The results confirm the opinion that active tubular secretion accounts for a large proportion of the total elimination of enprofylline.     

Nonlinear kinetics of propafenone metabolites in healthy man

Summary. The pharmacokinetics of oral and i. v. propafenone and its major metabolites have been investigated in 8 healthy subjects. The total body clearance of propafenone was 963 ml/min, the terminal half-life 198 min and its absolute bioavailability was 15.5%. The two active metabolites (5-hydroxypropafenone and N-depropylpropafenone) showed non-linear kinetics in that both the dose-corrected area under the serum concentration-time curve and the amount excreted in the urine were larger after oral dosing. This resulted in considerably higher serum concentrations of the metabolites despite comparable serum concentrations of the parent compound. Thus, the concentration-effect relationship in the same patient may differ after oral and intravenous doses if concentrations of the active metabolite(s) are not taken into consideration. Although the mechanism of the nonlinearity is not clear, the data indicate that it may be due to saturable biliary excretion of the metabolites.     

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