Dose-dependent kinetics of caffeine in rats

Caffeine was administered orally to male rats at 3 different doses (1, 10, 100 mg/kg). Plasma and brain concentrations were measured and kinetic parameters calculated. Ratios between doses were much lower than between areas under the curve in plasma as well as in brain. Brain:plasma ratios changed with the dose. Dose-dependent kinetics of caffeine in elimination and absorption is apparent.     

The pharmacokinetics of carbamazepine

Summary The time-courses of plasma carbamazepine concentrations were followed in six apparently healthy adult subjects who, at different times, took single oral drug doses of 200, 400, 500, 600, 700, 800 and 900 mg. There were some suggestions of impaired bioavailability of the drug when given in tablet form. The following values were obtained for various pharmacokinetic parameters:k _abs =0.176±0.209 h^–1;k=0.0203±0.0055 h^–1; T_1/2=37.5±13.1 h; V_D=0.825±0.1041 · kg^–1; Clearance=0.0163±0.0061 l · kg^–1. The elimination rate constant showed a statistically significant increase with increasing drug dose. This may help explain the clinical observation that the rate of rise of steady state plasma carbamazepine concentrations tends to decrease with dose increase in patients taking carbamazepine alone.     

The absolute bioavailability of caffeine in man

Summary The absolute bioavailability of orally administered caffeine was investigated in 10 healthy adult male volunteers, aged 18.8 to 30.0 years. The subjects were administered a 5 mg/kg dose of caffeine as either an aqueous oral solution or an intravenous infusion, on separate occasions about 1 week apart, in a randomized crossover fashion. Plasma samples were collected over the 24-h period following each dose and assayed for their caffeine content using a high-performance liquid chromatographic technique. The oral absorption was very rapid, reaching a peak (T_p) plasma concentration after 29.8±8.1 min (mean±SEM). In addition, the variation in the maximum plasma concentration (C_max) was low, 10.0±1.0 µg/ml. The absolute bioavailability was assessed by comparing the areas under the plasma concentration vs. time curves for the intravenous and oral doses of caffeine. The rapid absorption resulted in essentially complete bioavailability of the oral caffeine, F(%)=108.3±3.6%. The caffeine plasma half-lives varied from 2.7 to 9.9 h, indicating substantial inter-subject variability in its elimination.     

Plasma concentrations of pralidoxime methylsulphate in organophosphorus poisoned patients

Using pharmacokinetic data from healthy human volunteers in a bicompartmental pharmacokinetic model, a repeated dose scheme for pralidoxime methylsulphate (Contrathion^®) was developed producing plasma levels remaining above the assumed therapeutic concentration of 4 mg·1^–1. Using the same data, it was found that a concentration of 4 mg · 1^–1 could also be obtained by a loading dose of 4.42 mg · kg^–1 followed by a maintenance dose of 2.14 mg · kg^–1 · h^–1. In order to study the pharmacokinetic behaviour of pralidoxime in poisoned patients, this continuous infusion scheme was then applied in nine cases of organophosphorus poisoning (agents: ethyl parathion, ethyl and methyl parathion, dimethoate and bromophos), and the pralidoxime plasma levels were determined. The mean plasma levels obtained in the various patients varied between 2.12 and 9 mg·1^–1. Pharmacokinetic data were calculated, giving a total body clearance of 0.57±0.271· kg^–1· h^–1 (mean ± SD), an elimination half-life of 3.44±0.90 h, and a volume of distribution of 2.77±1.451 ·kg^–1.     

Pharmacokinetic studies with chlorthalidone (hygroton®) in man

Summary The kinetics of chlorthalidone in blood and urine were analysed in one group of 6 healthy volunteers after single oral doses of 50, 100 and 200 mg, as well as in a second group of 6 volunteers during and after daily oral doses of 50 mg for 14 days. The mean maximal concentrations recorded in blood 8 h after the three different doses were 3.15 µg/ml (SD±0.52), 5.55±1.58 µg/ml and 7.93±1.40 µg/ml, respectively. Disappearance of chlorthalidone from blood followed an apparent first order type of reaction, the average half life t₅₀ being 49 h (SD 11 h). Total renal elimination of unchanged chlorthalidone amounted to 53.3±8.7%, 46.1±8.4% and 34.0±7.3% of the single 50, 100 and 200 mg doses. Between the 6th and 14th days of daily treatment the concentration at the end of the 24 h dose interval was 7.2±1.4 µg/ml (± 1.4) in blood and 186±44 ng/ml in plasma. Except in the early absorption phase after each dose, the distribution of chlorthalidone between erythrocytes and plasma was constant, the average plasma concentration being 1.38±0.28% (n=75) of the whole blood concentration. At steady state during daily dosing with chlorthalidone 50 mg, the renal elimination of unchanged chlorthalidone within each 24 h dose interval was 57±11.2% of the daily dose. The renal plasma clearance ranged from 46 to 70 ml/min. Following termination of repeated administration the concentration of chlorthalidone in blood decreased with a t₅₀=50±5 h and in plasma with t₅₀=49±4.8 h.     

The effect of caffeine on human performance,alone and in combination with ethanol

The effect of caffeine (300 mg/70 kg) on cognitive, perceptual and motor functions was investigated both alone and in combination with ethanol (0.75 g/kg) in 68 healthy student volunteers of both sexes. A test battery consisting of standing steadiness, simple and complex reaction time, manual dexterity, numerical reasoning, perceptual speed and verbal fluency was used. Placebos for both drugs were included. Caffeine was administered in decaffeinated coffee immediately after finishing drinking the alcoholic beverage. A peak plasma ethanol concentration of 92 ± 4 mg/100 ml occurred at 40 min which was not modified by caffeine. Caffeine did not antagonise the ethanol-induced decrement in performance except in the reaction time tests. Caffeine alone caused a significant increase in body sway at 40 min.     

Human pharmacokinetics of tolfenamic acid,a new anti-inflammatory agent

Summary The pharmacokinetics of tolfenamic acid, a new anti-inflammatory agent was studied in six healthy volunteers after an intravenous dose of 100 mg and oral doses of 100, 200, 400 and 800 mg. The disposition of intravenous tolfenamic acid could be described by two-compartment open model, with a central compartment volume (V_dc) of 5.6±0.31 (mean±SE), volume during -phase (V_d) of 31±21, and a total elimination rate constant (k₁₀) 1.6±0.1 h^–1. The terminal elimination half-life was 2.5±0.6 h and the total plasma clearance 155±15 ml/min. The elimination occured principally by extrarenal mechanisms, the recovery of unchanged drug together with is glucuronide in urine averaging only 8.8% of the intravenous dose. The binding of tolfenamic acid to plasma proteins averaged 99.7%. The gastrointestinal absorption had a mean half-life of 1.7±0.1 h. Based on comparison of areas under the plasma concentration time-curves after intravenous and oral administration, the biovailability of tolfenamic acid capsules averaged 60%. The rate and extent of absorption and the rate of elimination of tolfenamic acid were independent of dose.     

Pharmacokinetics of single and multiple ascending doses of the antiallergic agent tiacrilast in man

Five groups of six healthy subjects received single oral doses of 150, 300, 450, 600 or 750 mg tiacrilast 150 mg capsules, followed 24 h later by the same dose given every 6 h for 7 days, in a study designed to assess the pharmacokinetics of single and multiple doses of tiacrilast. Plasma samples were obtained at specified times after the initial dose, after 4 days of multiple dosing and after the last dose of tiacrilast. Samples were assayed for unchanged drug by a specific HPLC method. Wide variability was seen in the plasma concentration-time data. Plasma concentrations and pharmacokinetic parameters were nearly proportional to dose over the 150 to 750 mg dose range studied. Moreover, there was no evidence of unexpected accumulation of the drug in the plasma during multiple dosing and food did not appear to alter the bioavailability of tiacrilast to any clinically significant extent. The apparent elimination half-life was similar after single and multiple doses and ranged from 1 to 3 h.     

Effects of caffeine on the kinetics of fluvoxamine and its major metabolite in plasma after a single oral dose of the drug

The effects of caffeine on the kinetics of fluvoxamine (FLV) and its major metabolite fluvoxamino acid (FLA) in plasma, after a single oral dose of the drug, were studied in 12 healthy male volunteers. The subjects received caffeine 300 mg/d or placebo for 11 days in a double-blind randomized crossover manner, and on the eighth day they received a single oral 50-mg dose of FLV. Blood sampling and pharmacodynamic evaluation were conducted up to 72 hours after FLV dosing. Plasma concentrations of FLV and FLA were measured by high-performance liquid chromatography. Caffeine significantly decreased the plasma concentrations at 6 time points (P<0.05) and total area under the plasma concentration-time curve (156.5+/-51.7 vs. 118.9+/-38.2 ng/h/mL, P<0.01) of FLV. Plasma concentration and pharmacokinetic parameters of FLA were not affected by caffeine. Caffeine induced no significant change in the pharmacodynamic effects of FLV. The present study suggests that caffeine slightly induces the metabolism of FLV, probably mediated by CYP1A2.     

Kinetics of a high dose of piretanide in renal failure

Summary The kinetics of piretanide was studied in patients with renal failure. After oral administration of a high dose of piretanide (96 mg), the pharmacokinetic parameters were: elimination rate constant 0.346±0.072 h^–1, half life 2.00±0.35 h, and total plasma clearance 119.55±35.90 ml · min^–1. Compared to the values obtained in adults with normal renal function, these results show a decrease in total plasma clearance, but conservation of the metabolic clearance which amounts to 45% of the total clearance in the healthy adult.     

Single and multiple dose pharmacokinetics of pindolol

Summary The pharmacokinetics of pindolol were studied in six healthy individuals following a single 10 mg dose (SD) and multiple (5 mg tid over 6 days) doses (MD). The plasma elimination half-life was identical after SD (4.7±0,8 h) and MD (4.1±1.1 h). Steady state plasma concentrations were reached after 36 h and remained stable thereafter. The variation in steady state concentrations was small in each individual and also between individuals. The steady state concentration of pindolol can be predicted from the pharmacokinetic data obtained after a single dose. The results of the present study suggest that the disposition of pindolol is linear over the concentration range studied.Supported by Deutsche Forschungsgemeinschaft (Gu 86/4)     

Inhibitory effects of propafenone on the pharmacokinetics of caffeine in humans

CYP1A2 is involved in the metabolism of both caffeine and propafenone, a class Ic antiarrhythmic agent. Despite the widespread consumption of caffeine, drug-drug interactions with this agent are often overlooked. This study investigated effects of propafenone on the pharmacokinetics of caffeine. Eight healthy volunteers were included in our study. A total of 300 mg of caffeine was given on 2 occasions, once alone and once during the coadministration of 300 mg propafenone. Serial blood samples were collected and pharmacokinetic parameters were estimated using a population pharmacokinetic approach. A one-compartment PK model with first-order absorption and elimination described plasma concentration profiles. Concomitant administration of propafenone decreased caffeine oral clearance from 8.3 +/- 0.9 L/h to 5.4 +/- 0.7 L/h (P < 0.05). Elimination half-life of caffeine was also increased 54% by propafenone. One of our volunteers was a poor metabolizer of CYP2D6. Concomitant administration of propafenone to this volunteer caused the greatest increase in caffeine plasma concentrations. These results support the concept of competitive inhibition between propafenone and caffeine. Our results suggest that propafenone causes significant inhibition of CYP1A2 activity leading to a decrease in the clearance of caffeine. Caffeine has intrinsic proarrhythmic effects; thus, its coadministration with an antiarrhythmic agent such as propafenone should be used with caution, especially in patients with poor CYP2D6 activity.     

Bioavailability of disopyramide in normal volunteers using unbound concentration

Summary The pharmacokinetics of disopyramide were determined in 10 healthy volunteers after a 300 mg oral dose and again after a 2mg/kg i.v. dose. The unbound clearance was 599 ml/min and the unbound renal clearance 310 ml/min. The terminal elimination rate constant of unbound drug was 0.180 h⁻¹ after the i.v. dose and 0.203 h⁻¹ after the oral dose. The absorption rate constant was 0.53⁻¹ and the maximum peak concentration occurred after 3.2 h. The bioavailability was 0.809 using the area under the unbound plasma concentration time curve. Although a saturable plasma protein binding was found in all subjects the bioavailability using the total concentration, in contrast to theoretical expectations, showed the same value (0.813) as the unbound concentrations.     

Caffeine disposition in obesity.

Caffeine pharmacokinetics were studied in 16 obese (mean +/- s.e. mean body weight; 110 +/- 8 kg; % ideal body weight (IBW); 186 +/- 14%) and 23 normal body weight (64 +/- 3 kg; 103 +/- 3% IBW) subjects. Eight obese and four control subjects were cigarette smokers. After abstaining from caffeine for 48 h and an overnight fast, each subject ingested 162 mg caffeine orally. Concentrations of caffeine were measured in plasma samples obtained during the 24 h following the dose and pharmacokinetic variables were determined. The apparent volume of distribution was increased markedly in obese subjects (69.9 +/- 5.9 vs 43.6 +/- 2.8 l; P less than 0.001) in the absence of any change in oral clearance (135 +/- 14-obese vs 112 +/- 12 ml/min; NS), resulting in a trend toward increased elimination half-life (7.05 +/- 1.08-obese vs 5.40 +/- 0.40 h; NS). Apparent volume of distribution correlated well with percent IBW (r = 0.65; P less than 0.001). Caffeine clearance, suggested as a measure of in vivo cytochrome P-448 activity in humans, was not altered in obesity. In contrast, the extent of caffeine distribution increased in direct relation to body weight. If caffeine is used therapeutically, the loading dose should be calculated as a function of total body weight. Since clearance of caffeine is not related to body weight, these data indicate that a chronic dosing regimen to maintain a given plasma caffeine concentration should not be altered due to obesity.     

Safety and pharmacokinetics of mifentidine after increasing oral doses in healthy subjects

Summary Eight healthy men were each given single oral doses of mifentidine 20, 40 and 80 mg, a new H₂-receptor antagonist, in a four-way, double-blind, placebo-controlled, cross-over, dose-proportionality study.No significant objective or subjective effects were noted. Mifentidine showed unusual pharmacokinetic behaviour, producing a significant secondary peak in the drug concentration profile. The plasma AUC of mifentidine increased linearly with dose (r=0.983). The apparent plasma clearance was 38.11·h^–1, 31.01·h^–1, and 47.41·h^–1 for the 20, 40 and 80 mg doses, respectively, and the corresponding terminal plasma half-lives were 10.3 h, 12.0 h, and 8.6 h. About 20% of the parent drug was excreted in urine over 24 h. The renal clearance (9.41/h for 20 mg, 9.5 l/h for 40 mg, and 12.8 l/h for 80 mg mifentidine) indicates that some of the drug was excreted by active tubular secretion.The results indicate that mifentidine is safe after single oral doses up to 80 mg. The pharmacokinetics of the 20 and 40 mg doses were similar, but after 80 mg the total body and renal clearances were significantly greater than after the two lower doses. As the terminal plasma half-life of mifentidine is longer than of other available H₂-receptor antagonists, it may have clinical implications for once-a-day therapy of peptic ulcer diseases.     

Pharmacokinetics of carbamazepine in normal humans after single and repeated oral doses

The pharmacokinetic profile of carbamazepine was studied in six normal humans after single and repeated oral doses. The plasma concentrations following single dose (100, 200, 600 mg) were fitted by a one-compartment open model. Using area as a measure, availability was constant in the dose range studied. The elimination half-life ± SEafter a single dose was 37.7±5.7hr; it decreased during chronic treatment to a calculated value around 21 hr. The steady-state plasma concentration, lower than expected from the single-dose study, was adequately predicted from the single-dose data when a correction was made for the increased elimination rate constant. The present findings contrast with the apparently unpredictable plasma levels reported during carbamazepine therapy.     

Pharmacokinetics of paraxanthine, one of the primary metabolites of caffeine, in the rat

The pharmacokinetic of paraxanthine, one of the primary metabolites of caffeine, is described for the first time. Groups of adult male rats were given different doses of paraxanthine as iv bolus injections. Blood cell/plasma partition and the binding of the compound to rat plasma proteins (determined by equilibrium dialysis) were investigated. The fraction bound (15%) remained constant in the concentration range of 1-100 micrograms/ml. Partition was also constant over a wide range of doses. Up to the 10 mg/kg dose, the paraxanthine followed first order kinetics and blood concentrations vs. time data were described by a one-compartment, open model system. The mean half-life and elimination rate constant were 1 hr and 0.70 hr-1, respectively. The average apparent volume of distribution was 1.50 liters/kg and total clearance was 0.90 liter/hr/kg. After larger doses (15 and 30 mg/kg), kinetics were nonlinear. The area under the blood concentration-time curve increased, but not in proportion to the dose, and modifications of pharmacokinetic parameters were shown. These findings indicate that in the rat paraxanthine is eliminated by a saturable process with an apparent Km of about 31 micrograms/ml and an apparent Vmax of about 0.40 micrograms/ml/min. Close estimates were obtained by two different methods of calculation. Our results suggest that the pharmacokinetic profile of paraxanthine could be important to understand the kinetics and the potential toxic effects of its parent compound, caffeine, in animals and man.     

Artemisinin pharmacokinetics in healthy adults after 250, 500 and 1000 mg single oral doses

Eight healthy male, Vietnamese subjects were administered 1×250, 2×250 and 4×250 mg artemisinin capsules in a cross-over design with randomized sequence with a 7-day washout period between administrations. The inter-individual variability in artemisinin pharmacokinetics was large with parameter coefficients of variation (CV) typically between 50–70%. The parameter with the smallest variability was the elimination half-life (CV≈30–40%). Analysis of variance indicated also a large intra-subject variability (CV≤24%) for the dose-normalized area under the plasma concentration–time curve (AUC/dose). The pharmacokinetic results suggested artemisinin to be subject to high pre-systemic extraction. Artemisinin half-life could not predict the extent ofin vivo exposure to the drug, there being no correlation between half-life and oral clearance. Artemisinin oral plasma clearance was about 400 L h⁻¹ exhibiting a slight decrease with dose, although the effect was weak. Thus results from studies using different artemisinin doses may, within the studied dose range, be compared without the complication of disproportionate changes in drug exposure with varying dose levels. Half-lives appeared to increase with dose. An observed period effect in the analysis of variance was tentatively associated with time-dependency in artemisinin pharmacokinetics. There was a high correlation between artemisinin plasma concentrations determined at various time-points after drug administration and the AUCs after the 500 and 1000 mg doses, but less so after the 250 mg dose. This may show a tentative approach to assess the systemic exposure of the patients to artemisinin from the determination of artemisinin plasma concentrations in one or two plasma samples only. Artemisinin was well tolerated with no apparent dose or time dependent effects on blood pressure, heart rate or body temperature. © 1998 John Wiley & Sons, Ltd.     

Medifoxamine: Oral tolerance and pharmacokinetic study in healthy human volunteers

Summary Medifoxamine is a monoamine reuptake inhibiting antidepressant drug. We have investigated its pharmacokinetics in normal healthy volunteers. After an overnight fast, ascending doses of 200, 500, 750 and 1000 mg of medifoxamine were taken orally. Plasma samples were analysed using a specific HPLC method.Medifoxamine was well tolerated and exhibited a first order linear pharmacokinetic profile. It underwent rapid absorption and peak plasma concentrations were achieved about 1.0 h after administration. Thereafter the elimination profile was biphasic with a mean terminal half life less than 3 hours.We found a linear relationship (r=0.80) between administered dose and AUC values for the four doses. High values were obtained for the apparent volumes of distribution and the plasma clearance.     

Zolpidem 10 mg given at daytime is not antagonized by 300 mg caffeine in man

Objective: Caffeine counteracts various effects of traditional benzodiazepines (BZDs). As zolpidem, a short-acting hypnotic, is an atypical GABA_A-BZD agonist, we investigated when caffeine would counteract the effects of zolpidem as well. Methods: In daytime study I, zolpidem 10 mg (capsule) and caffeine 150 or 300 mg (in decaffeinated coffee) were given, alone and in combinations, to parallel groups (n= 15–17) of healthy students in double-blind and placebo-controlled manner. Objective and subjective tests were done before and 45 min and 90 min after intake. Ranked Δ values (changes from baseline) were analysed by one-way contrast ANOVA and Scheffe's tests. In daytime study II, four healthy subjects took zolpidem 10 mg alone, and together with blinded caffeine 250 mg or (at −45 min) erythromycin 750 mg. Objective and subjective effects were measured and plasma zolpidem concentrations assayed at baseline and 45 min and 90 min after zolpidem intake. Results: In study I, practice effects after placebo (ad + 30%) were seen for letter cancellation and digit symbol substitution but not for flicker fusion tests. Zolpidem alone significantly impaired (P < 0.05 vs Δ-placebo) letter cancellation and digit symbol substitution at 45 min and 90 min, lowered the flicker fusion threshold at 45 min, and caused subjective drowsiness, mental slowness, clumsiness and feeling of poor performance. Caffeine alone showed a non-significant trend to improve objective performance. The combined effects of zolpidem and either dose of caffeine matched those measured after zolpidem alone. Zolpidem + caffeine 300 mg was not stronger than zolpidem + caffeine 150 mg in impairing immediate memory and causing subjective sedation. In study II, zolpidem caused objective and subjective sedation; neither caffeine nor erythromycin modulated the effects of zolpidem or plasma zolpidem concentrations. Conclusion: The sedative effects of 10 mg of zolpidem are not antagonized by 150–300 mg of caffeine in pharmacodynamic or pharmacokinetic terms. Received: 15 December 1997 / Accepted in revised form: 11 March 1998