Disposition Rate Constants Research Articles

Evaluation of the Single-dose Pharmacokinetics of Bilastine in Subjects with Various Degrees of Renal Insufficiency

BackgroundBilastine is a novel second-generation H1 antihistamine, which has not shown sedative or cardiotoxic effects in clinical trials and in post-marketing experience so far, developed for the symptomatic treatment of allergic rhinoconjunctivitis and urticaria. It has recently been granted marketing authorization for these therapeutic indications in adults and adolescents at a once-daily oral dose of 20 mg in several European countries.ObjectiveThis study was conducted to determine the pharmacokinetics of bilastine at a single oral dose of 20 mg in renally impaired subjects. The need for a dose adjustment in patients with renal insufficiency was assessed by comparing the exposure to bilastine in these subjects with the estimated exposure of a dose corresponding to the safety margin.MethodsThe study was an open-label, single-dose, parallel-group study of the pharmacokinetics and safety of a single dose of bilastine. The study was conducted as an in-patient setting at a clinical pharmacology facility. A total of 24 male or female subjects aged 18–80 years were to be enrolled in four groups of six subjects each. The groups were as follows: (1) healthy [glomerular filtration rate (GFR) >80 mL/min/1.73 m2]; (2) mild renal insufficiency (GFR 50–80 mL/min/1.73 m2); (3) moderate renal insufficiency (GFR 30–50 mL/min/1.73 m2); and (4) severe renal insufficiency (GFR ≤30 mL/min/1.73 m2). A single 20 mg bilastine tablet was administered in a fasted state. Blood and urine samples were collected from pre-dose up to 72 h post-dose for bilastine pharmacokinetic analysis. Pharmacokinetic results were summarized using appropriate descriptive statistics.ResultsThere was a clear trend of increasing area under the plasma concentration–time curve (AUC) and maximum plasma concentration (Cmax) through the groups 1–4. The mean AUC from time zero to infinity (AUC∞) ranged from 737.4 to 1708.5 ng·h/mL in healthy subjects and severely impaired subjects, respectively. No significant differences among groups in median time to reach Cmax (tmax) or in the mean terminal disposition rate constants for bilastine were found. Renal and plasma clearance paralleled GFR. In all groups of renally impaired subjects the corresponding 90 % confidence interval of both AUC∞ and AUC from time zero to time of last measurable plasma concentration (AUClast) were not within the 0.8–1.25 interval, indicating that bioequivalence between groups could not be demonstrated. The majority of bilastine was excreted within the first 12 h, and elimination was essentially complete by 72 h.ConclusionAn oral dose of bilastine (20 mg) was well-tolerated in renal insufficiency, despite the increase in exposure. The oral plasma clearance to renal clearance ratio [(CLP/F)/CLR] was approximately equal in the different groups, suggesting that renal excretion was the main elimination route for bilastine, and no alternative elimination routes were used even in severe renal insufficiency. Although exposure to bilastine was higher in renally impaired subjects, it remained well within the safety margins, thus allowing the conclusion that a 20-mg daily dose can be safely administered to subjects with different degrees of renal insufficiency without the need for dose adjustments.

A single-dose, randomized, two-way crossover study comparing two olanzapine tablet products in healthy adult male volunteers under fasting conditions

Background: Olanzapine is a psychotropic agent that belongs to the thienobenzodiazepine class. Objective: The aim of this study was to assess the bioequivalence of 2 commercial 10-mg tablet formulations of olanzapine by statistical analysis of the pharmacokinetic parameters C max, AUC from 0 to 72 hours after dosing (AUC 0-72), and AUC 0-∞ as required by the Egyptian health authority for the marketing of a generic product. Methods: This bioequivalence study was carried out in healthy male volunteers using a single-dose, randomized, 2-way crossover design under fasting conditions. Statistical analysis of the pharmacokinetic parameters C max, AUC 0-72, and AUC 0-∞ was conducted to determine bioequivalence (after log-transformation of data using analysis of variance and 90% CIs) and to gain marketing approval in Egypt. The formulations were considered to be bioequivalent if the log-transformed ratios of the 3 pharmacokinetic parameters were within the predetermined bioequivalence range (ie, 80%–125%), as established by the US Food and Drug Administration (FDA). Both the test product (Trademark: Integrol ® [Global Napi Pharmaceuticals, Cairo, Egypt]) and the reference product (Trademark: Zyprexa ® [Eli Lilly and Company, Basingstoke, Hampshire, United Kingdom]) were administered as 10-mg tablets with 240 mL of water after an overnight fast on 2 treatment days, separated by a 2-week washout period. After dosing, serial blood samples were collected for 72 hours. Plasma samples were analyzed using a sensitive, reproducible, and accurate liquid chromatography-tandem mass spectrometry method capable of quantitating olanzapine in the range of 0.167 to 16.7 ng/mL, with a lower limit of quantitation of 0.167 ng/mL. Adverse events were reported by the volunteers as instructed or observed by the resident physician, and were recorded, tabulated, and evaluated. Results: Twenty-four healthy adult male volunteers participated in this study. Their mean (SD) age was 24.7 (6.2) years (range, 19–41 years), mean weight was 73.4 (6.7) kg (range, 64–89 kg), and mean height was 174.25 (4.6) cm (range, 168–186 cm). Values for C max, AUC 0-72, AUC 0-∞, T max, t 1/2, and the terminal disposition rate constant were found to be in agreement with previously reported values. The differences between the 2 products did not reach statistical significance at P ≤ 0.05 (90% CIs: C max, 101.82–124.79; AUC 0-72, 93.36–102.04; and AUC 0-∞, 88.57–101.77). The test/reference ratio of these parameters was within the acceptance range of the FDA criterion for bioequivalence. Both formulations were apparently well absorbed from the gastrointestinal tract (ie, no specific gastrointestinal tract-related adverse events were reported). Conclusions: In this small study in healthy male volunteers, there were no statistically significant differences in any of the calculated pharmacokinetic parameters between the 10-mg test and reference tablets of olanzapine. The 90% CIs for the ratios of mean C max, AUC 0-72, and AUC 0-∞ were within the range of 80% to 125% (using log-transformed data), meeting the FDA regulatory criterion for bioequivalence. Both formulations were well tolerated.

Pharmacokinetics of Mycophenolic Acid in Live Donor Liver Transplant Patients vs Deceased Donor Liver Transplant Patients

The exposure of mycophenolic acid in live donor liver transplant patients (those receiving a partial hepatic volume) in comparison to deceased donor liver transplant patients (those receiving the whole hepatic volume) after administration of mycophenolate mofetil has not been reported earlier. The aim of the present study is to compare the pharmacokinetics parameters of mycophenolic acid and mycophenolic acid glucuronide in live donor liver transplant patients versus deceased donor liver transplant patients. Twelve live donor liver transplant and 12 deceased donor liver transplant recipients were studied over a dosing interval after intravenous administration of mycophenolate mofetil. The maximum concentration (Cmax) and the area under the plasma concentration versus time curve (AUC) for mycophenolic acid in live donor liver transplant patients were significantly higher than in deceased donor liver transplant patients (Cmax/AUC: live donor liver transplant patients: 16.1 +/- 6.6 microg/mL/43.9 +/- 12.6 microg/mL.h vs deceased donor liver transplant patients: 10.7 +/- 2.0 microg/mL/28.9 +/- 7.1 microg/mL.h; P = .046/.002). The volume of distribution was higher in the deceased donor liver transplant patients compared with live donor liver transplant patients. However, the mean plasma concentration at 12 hours (Clast), drug disposition rate constant, half-life (t 1/2), and mean residence time were similar in both groups. The mean plasma concentration of mycophenolic acid glucuronide was 1.4 to 2.0 times higher in deceased donor liver transplant patients compared with live donor liver transplant patients. These observations point to the need to use a lower dosage (approximately 30%) of mycophenolate mofetil in live donor liver transplant patients compared with deceased donor liver transplant patients.

Modeling the metabolic effects of terbutaline in beta2-adrenergic receptor diplotypes.

Our objective was to determine whether beta(2)-adrenergic receptor polymorphisms influence terbutaline-stimulated changes in glucose, insulin, and potassium concentrations in healthy adults. Seven healthy adults homozygous for the Arg-19/Gly16/Glu27 haplotype (RGE) and seven homozygous for the Cys-19/Arg16/Gln27 haplotype (CRQ) volunteered to receive a 1-hour infusion of terbutaline (0.01 mg/kg). A 2-compartment pharmacokinetic model was fitted to the terbutaline concentrations. Concentrations of glucose and insulin were fitted simultaneously by use of a coupled feedback indirect response model. An indirect response model was also fitted to the plasma potassium concentration versus time data. The -2 log-likelihood ratio test was used to determine whether estimates of the covariates of diplotype and sex improved the model fittings. Demographic variables, anthropometric characteristics, and pharmacokinetics did not differ by diplotype. The coupled feedback model fitted the glucose and insulin concentration data well with excellent precision. Terbutaline stimulated production of glucose (S(1)) to a greater extent in RGE compared with CRQ diplotypes, as follows: S(1) = 0.039 +/- 0.007 (mean +/- SD) versus 0.0276 +/- 0.01, respectively (P <.05, -2 log-likelihood criterion). The baseline values, disposition rate constants for glucose (k(out1)) and insulin (k(out2)), production rate of insulin (S(2)), feedback effect of insulin on glucose (S(3)), and pharmacodynamic parameters for potassium did not differ by diplotype or sex. The beta(2) receptor diplotype influences receptor-stimulated glucose production in healthy, nonobese individuals, which is consistent with beta(2) receptor-mediated hepatic glycogenolysis. Future metabolic studies of this system should consider beta(2) receptor genetic variants.

Pharmacokinetic parameter transformations for educational simulations

SANTANDER-02-05 Simulations developed for training of healthcare professionals typically use computerized mathematical models of human physiology and pharmacology. Educational simulations may involve many drugs and patient groups. Pharmacokinetic (PK) data in the scientific literature are presented in a wide variety of PK parameter set formats. This complicates the incorporation of PK data in a simulation model with a given structure and associated parameter format. To solve this problem, we defined three sets of independent parameters, referring as much as possible to the pharmacokinetic literature [1], and localized and/or derived the analytical relationships between them. Methods:Figure 1 shows the names of the defined parameter sets and the transformations between them, and Tables 1 and 2 define the 'Clinical' and 'Base' sets for 2nd order PKs, respectively.Figure 1: Pharmacokinetic parameter sets and transformations.Table 1: Second order clinical set.Table 2: Second order base set.Strictly speaking, half-life is the time required for the plasma concentration to be reduced by 50%. The half-times used in the clinical set directly refer to the individual exponentials and disposition rate constants of the response to a unit bolus dose: which is the model underlying the base set. The relationships between the half-times and the disposition rate constants reflect this observation. Assuming that the plasma concentration data can be described by the parametric bolus response function we can calculate the areas under the concentration-time curve and under the first moment of the concentration time curve, respectively [1]. The parameter A1 is derived from the clinical set based on this observation. Results:Table 3 shows examples of derived transformations.Table 3: Parameter transformations from the second order clinical set to the second order base set.The complete analytical relationships between the parameter sets for first, second, and third order PKs facilitate the incorporation of diverse pharmacokinetic data in educational simulations. Acknowledgements: This work was funded in part by a grant from Medical Education Technologies, Inc., Sarasota, Florida, USA. The Fundação para a Ciência e a Tecnologia, of the Portuguese Ministry of Science and Technology provided funds for participation in this conference.

Pharmacokinetics of d, l-3-hydroxy-3-ethyl-3-phenylpropionamide (HEPP) in pregnant rats at different stages of gestation and maternal–fetal disposition during late pregnancy

The pharmacokinetics of d, l-3-hydroxy-3-ethyl-3-phenylpropionamide (HEPP), an investigational anticonvulsant drug, was evaluated in nonpregnant and in pregnant rats on gestation day (GD) 7, 12, and 21 after an intraperitoneal (i.p.) dose of 50 mg/kg. Maternal–fetal disposition in the GD21 group was also evaluated. In all groups, HEPP was rapidly absorbed and the disposition was well described by an open two-compartment kinetic model. The most pronounced effects of pregnancy on the kinetics of HEPP were observed at GD21 in which significant increases in the first-order hybrid disposition rate constants α and β, with corresponding decreases in half-lives were observed. Gestation also affected the intercompartmental transfer rate constants k 12 and k 21, specially at GD12 and at GD21. These changes could be associated with the physiologic increases in blood flow and cardiac output of pregnancy. There was also a slight decrease in the apparent volume of distribution at GD21, and a progressive decrease in the clearance values normalized by the body weight. No other significant differences in kinetic parameters were observed. On GD21, HEPP rapidly transfers from maternal blood to fetuses, to reach concentrations in the placenta and fetuses slightly higher than those of the maternal plasma (fetal:maternal ratio ranging from 1.07 to 1.45). After equilibrium, the concentrations in maternal, placental, and fetal tissues decreased in parallel.

Pharmacokinetics of 125I-labelled IgG, F(ab′) 2 and Fab fractions of scorpion and snake antivenins: merits and potential for therapeutic use

The immunoglobulin fractions IgG, F(ab′) 2 and Fab of scorpion and snake antivenoms possess pharmacokinetic characteristics that are significantly different from their respective venoms. The venoms (and their toxins) are several fold faster in their distribution into the tissues than any of the immunoglobulin fraction. In rabbits, F(ab′) 2 possessed the fastest disposition rate constants and the longest distribution half lives. In the physiologically based pharmacokinetic experiments carried out in mice F(ab′) 2 possessed the highest Cp max, smallest AUC and the shortest t 1/2 β in the different tissues while Fab had values in between IgG and F(ab′) 2. Rescue experiments in anaesthetized rats challenged with lethal doses of venoms or toxins and infused with border-line neutralizing doses of antivenoms, showed that rats infused with F(ab′) 2 completely recovered, those infused with IgG partially rescued and none of the rats infused with Fab survived. It is concluded that F(ab′) 2 of scorpion and snake antivenoms possess pharmacokinetic characteristics that render it the most suitable for use in serotherapy of scorpion and snake envenoming.

Anterior chamber and vitreous fluorescein kinetics in normal and diabetic subjects.

Describe and compare drug exchange between various parts of the eye. Fluorophotometric measurements of the anterior chamber, vitreous and plasma fluorescein concentrations were performed and subjected to a kinetic two-compartment analysis. The overall barrier properties as revealed by a permeability-index were found to be 12.2% and 3.5% for the anterior chamber and the vitreous, respectively. The apparent rate constant of permeation into the anterior chamber was found to be significantly higher than into the vitreous and the apparent peripheral body compartment. The terminal rate constant of fluorescein disposition from the anterior chamber was in agreement with the terminal disposition rate constant for plasma fluorescein, whereas elimination from the vitreous was significantly slower. Compartment analysis of ocular fluorescein kinetics is suitable for the study of anterior and posterior barrier properties in the eye. In this study fluorescein elimination from the anterior chamber was restricted by terminal plasma fluorescein decay rather than by ocular tissue.

Determination of the population pharmacokinetic parameters of sustained-release and enteric-coated oral formulations, and the suppository formulation of diclofenac sodium by simultaneous data fitting using NONMEM.

Data from sustained-release and enteric-coated oral formulations, and the suppository formulation of diclofenac sodium are fitted simultaneously using NONMEM and the general linear model, ADVAN 5. Absorption and disposition parameters, serum levels, and absorption profiles were determined. The in vivo absorption profiles were determined using the program TOPFIT. The in vivo absorption for the sustained-release formulation is slow first order and follows a flip-flop model since disposition rate constants are greater than absorption rate constants. Absorption from the enteric-coated form is essentially complete (> or = 95%) at about 7.5 h, while it is 95% complete at 24 h from the sustained-release formulation. This suggests likely absorption from the colon in the case of the sustained-release formulation since absorption is only 75% complete during the first 10 h. The sustained-release relative bioavailability is 90-99%. Absorption from the suppository is essentially complete at about 4.5 h. However, the relative bioavailability of the suppository formulation is low (55%), since defecation may remove the drug from the absorption site before complete absorption.

Pharmacokinetics of 125I-labelled Walterinnesia aegyptia venom and its specific antivenins: flash absorption and distribution of the venom and its toxin versus slow absorption and distribution of IgG, F(ab′) 2 and F(ab) of the antivenin

A three-compartment open pharmacokinetic model best fitted the data obtained following the i.v. injection of the venom, toxin and the immunoglobulin fractions into either rabbits or mice. The venom and toxin, however, possessed pharmacokinetic characteristics that were significantly different from the immunoglobulin fractions. The venom and toxin had very highly significantly greater disposition rate constants to the shallow and deep tissue compartments and overall elimination rate constant from the central compartment than any of the immunoglobulin fractions. This was reflected in other pharmacokinetic parameters, including highly significantly smaller areas under the curve (AUC) and highly significantly greater volumes of the central compartment ( V c), shallow tissue compartment ( V t shallow), deep tissue compartment ( V t deep) and total body clearance (TBC). In rabbits, F(ab′) 2 possessed the fastest disposition rate constants and the shortest distribution half-lives, while Fab showed the slowest disposition rate constants and the longest distribution half-lives. The same picture occurred in mice except that the values for Fab were between those of F(ab′) 2 and IgG. The time needed by the venom and toxin to reach maximum tissue concentration ( t max) ranged between 7 and 15 min and 60 and 180 min for the shallow and deep tissue compartments, respectively. The immunoglobulin fractions required 8–26-fold these times to attain t max; F(ab′) 2 was the fastest to achieve its maximal concentration. Following i.m. injection, very fast absorption of venom and toxin took place, with the toxin reaching t max within 5–20 min and 90% of the injected dose absorbed within 60 min. The bioavailability factor ( F) was 0.82 and 0.88 for the venom and toxin, respectively. Fab had an F-value of 0.36 and required 4.3 and 47.4-fold the time taken by the venom and toxin to achieve t max. The calculated values of F for F(ab′) 2 and IgG were 0.25 and 0.26, respectively. In the physiologically based pharmacokinetics (PBPK), the venom and toxin reached t max in the different organs studied very rapidly while the immunoglobulin fractions required several-fold this time to attain t max. F(ab′) 2 possessed the highest Cp max, the smallest AUC and the shortest t 1/2 β in the different tissues; Fab had values between F(ab) 2 and IgG. It is concluded that F(ab′) 2 possesses pharmacokinetic characteristics that render it most suitable for use in serotherapy of snake and scorpion envenoming. It should be injected i.v. in doses higher than calculated neutralizing doses to compensate for the slow rate of distribution. Because of slow and incomplete absorption, the i.m. injection of the immunoglobulin fractions would be of little value in serotherapy.

Population pharmacokinetic analysis of mizolastine and validation from sparse data on patients using the nonparametric maximum likelihood method.

A population analysis of the kinetics of mizolastine was performed from concentrations on 449 allergic patients, using the nonparametric maximum likelihood method (NPML). A two-compartment open model with zero-order absorption was used to describe the kinetics of mizolastine after oral administration. A heteroscedastic variance model was assumed for the error. To explain the kinetic variability, eight covariates were introduced in the analysis: gender, pharmaceutical dosage form, age, body weight, serum creatinine concentration, creatinine renal clearance, plasma levels of hepatic transaminases ASAT and ALAT. Their relationships to the kinetic parameters were studied by means of the estimated distribution of each kinetic parameter conditional on different levels of each covariate. An important interindividual kinetic variability was found for all parameters. Moreover, several kinetic parameters among which the duration of absorption were found to be influenced by pharmaceutical dosage form and gender. Body weight and creatinine renal clearance were found to have a little influence on the oral clearance and the smallest disposition rate constant. This population analysis was validated on a separate group of 247 other patients. For each observed concentration of this sample, a predictive distribution was computed using the individual covariates. Predicted concentrations and standardized prediction errors were deduced. The mean and variance of the standardized prediction errors were, respectively, 0.21 and 2.79. Moreover, in the validation sample, the predicted cumulative distribution function of each observed concentration was computed. Empirical distribution of these values was not significantly different from a uniform distribution, as expected under the assumption that the population model estimated by NPML is adequate.

Variation of the peak concentration following single and repeated drug administrations in investigations of bioavailability and bioequivalence

Contrasts were evaluated for the maximum blood or plasma concentration (C max) of drugs measured after repeated and single oral administrations. Variances C max of were calculated and also simulated for a single drug as well as the comparison of two formulations, i.e., for the analysis of investigations of both bioavailability and bioequivalence. The coefficient of variation (C V) of C max was higher in the steady state than after a single drug administration when the variability of the disposition rate constant (k) was substantially larger than that of the absorption rate constant (ka )In turn, the CV of C max was substantially lower following repeated than after single drug administration when the variability of ka dominated that of k.The latter condition often prevails in practice since the relative variation of absorption rates generally substantially exceeds that of clearance (the latter being proportional to k) The statistical insensitivity is superimposed on the low kinetic sensitivity exhibited by C maxfollowing repeated drug administrations. Consequently, bioequivalence trials conducted in the steady state generally permit a declaration of equivalence even between drug products that have very different absorption rates

Utilization of intravenously infused thiamin hydrochloride in healthy adult males

The utilization of intravenously administered thiamin hydrochloride in humans was assessed. One hundred mg (0.297 mmol) of thiamin hydrochloride was given by continuous infusion to 10 healthy males. The concentration versus time curves of thiamin and its phosphate esters in blood plasma, erythrocytes and urine were analyzed by high-performance liquid chromatography over a period of 240 hours. The phosphorylated forms of thiamin were assessed as total phosphates. By the end of infusion, non-phosphorylated thiamin reached its maximal plasma concentration (1106.5 nmol/l). Elimination of free thiamin followed a tri-exponential function with disposition rate constants of 4.56, 0.56, and 0.01 per h. Low concentrations of thiamin phosphates (Conc max = 71.5 nmol/l) were observed in blood plasma (t max = 6.3 h). Free thiamin but no phosphorylated metabolites were recovered in urine (0.213 mmol). In spite of rapid renal thiamin excretion, a large proportion of the infused vitamin was accumulated and metabolized to thiamin phosphates in erythrocytes (Conc max = 631.8 nmol/l; t max = 6.5 h). Rate constants of absorption (k a = 0.224 per h) and disposition (k el = 0.074 per h) were calculated for erythrocytes.

Stepwise determination of multicompartment disposition and absorption parameters from extravascular concentration-time data. Application to mesoridazine, flurbiprofen, flunarizine, labetalol, and diazepam

When disposition is monoexponential, extravascular concentration-time (C, t) data yield both disposition and absorption parameters, the latter via the Wagner-Nelson method or deconvolution which are equivalent. Classically, when disposition is multiexponential, disposition parameters are obtained from intravenous administration and absorption data are obtained from extravascular C, t data via the Loo-Riegelman or Exact Loo-Riegelman methods or via deconvolution. Thus, in multiexponential disposition one assumes no intrasubject variation in disposition, a hypothesis that has not been proven for most drugs. Based on the classical two- and three-compartment open models with central compartment elimination, and using postabsorptive extravascular C, t data only, we have developed four equations to estimate k10 when disposition is biexponential and two other equations to estimate k10 when disposition is triexponential. The other disposition rate constants are readily obtained without intravenous data. We have analyzed extravascular data of flurbiprofen (12 sets), mesoridazine (20 sets), flunarizine (5 sets), labetalol (9 sets), and diazepam (4 sets). In the case of diazepam intravenous C, t data were also available for analysis. After disposition parameters had been estimated from the extravascular data the Exact Loo-Riegelman method with the Proost modification was applied to the absorptive extravascular data to obtain AT/VP as a function of time. These latter data for each subject and each drug studied were found to be fitted by a function indicating either simple first-order absorption, two consecutive first-order processes, or zero-order absorption. After absorption and disposition parameters had been estimated, for each set of extravascular data analyzed, a reconstruction trend line through the original C, t data was made. The new methods allow testing of the hypothesis of constancy of disposition with any given drug. There is also a need for new methods of analysis since the majority of drugs have no marketed intravenous formulation, hence the classical methods cannot be applied.

Carvedilol increases the systemic bioavailability of oral digoxin.

The effects of a single oral dose of 25 mg carvedilol on the plasma and urinary kinetics of digoxin after an oral and intravenous 0.5 mg dose, were investigated in two separate double-blind, placebo-controlled, period-balanced cross-over studies in healthy male subjects. Carvedilol increased the mean maximum plasma concentration and the area under the plasma concentration time-curve of digoxin when administered orally. The effects were virtually confined to the first 4 h after dosing, and the apparent terminal disposition rate constant was not changed. Carvedilol did not alter the plasma and urinary kinetics of intravenously administered digoxin.

Dse and Limitations of the Truncated Area Under the Curve in Bioequivalence Testing

AbstractComputer simulations were used to evaluate the truncated area under the plasma level-time curves (AUC.) as indicators of the bioequivalence between test and reference products. Plasma concentrations were simulated from one and two compartment open models using first order absorption rate constants (Ka) and bioavailability (F) ranging respectively from 45 to 200% and 60 to 140% of the reference values. The pharmacokinetic parameters were selected to cover a wide range of disposition rate constants (0.01-0.79 hr.−1). The area under the blood level-time curves was calculated using the trapezoidal rule at each time point (t) according to a conventional sampling regimen. The extent of absorption (AUC.inf) was calculated, using integrals of the general blood equations. The ratios of AUC.: test to reference and AUCL to AUC.were determined. For most simulations, the ratios changed very little between the end of the absorption period, the last time point and the time infinity. AUC, was not a good parameter...

Pharmacokinetics of furegrelate after oral administration to normal humans.

Furegrelate sodium is a thromboxane synthetase inhibitor with potential for the treatment of various diseases including hypertension, thrombosis, and renal disorders. The absorption and disposition of the parent drug in normal male volunteers have been studied after single- and multiple-dose oral administration. The results from the single-dose study indicate that furegrelate is rapidly absorbed, with a Tmax of 1.0-1.7 hr, has an apparent terminal disposition rate constant of 0.12-0.17 hr-1, and is eliminated primarily by the kidney, with 62-78% of the dose excreted as parent drug. After multiple-dose oral administration for 4.5 days using a b.i.d. dosing regimen, no apparent change in the absorption, disposition, and elimination kinetics is detected and only a slight potential for drug accumulation is observed.

The pharmacokinetics of dichloromethane. II. Disposition in fischer 344 rats following intravenous and oral administration

The tissue distribution and metabolism of dichloromethane (DCM; CH 2Cl 2) was investigated in Fischer 344 rats following iv or oral administration. The route and level of exposure were found to have a significant effect on the disposition characteristics. A two-compartment model was used to describe the elimination of DCM from blood following single iv doses. The estimates of t 1 2 ,β were 11.9 and 23.5 min for doses of 10 and 50 mg/kg, respectively, and the disposition rate constants, β were found to differ significantly at P < 0.05. When DCM was administered orally (by gavage) in a daily dose of 50 or 200 mg/kg for 14 consecutive days, rapid absorption and distribution to the tissues characterized the disposition. Dose-dependent metabolism to 14CO 2 and 14CO and rapid pulmonary clearance of unchanged 14CH 2Cl 2 were the dominant routes of elimination of DCM from the body following both iv and oral doses. No observable pharmacokinetic or metabolic effect resulted from repeated oral dosing.

Cyclosporine kinetics in renal transplantation

The pharmacokinetics of cyclosporine were evaluated in 41 recipients of a cadaveric renal transplant. Cyclosporine was taken by mouth (mean dose 14 mg/kg) on one study day and was intravenously infused over 2 hours (mean dose 4.7 mg/kg) on the next study day. Cyclosporine was extracted from whole blood and analyzed by HPLC. After intravenous infusion, cyclosporine exhibited multicompartmental behavior. The mean (+/- SD) terminal disposition rate constant was 0.065 +/- 0.036 hours-1 and the harmonic mean t 1/2 was 10.7 hours. The harmonic mean total body clearance of cyclosporine was 5.73 ml/min/kg and the mean apparent volume of distribution was 4.5 +/- 3.6 L/kg. The absorption of oral cyclosporine was slow and incomplete. Peak blood cyclosporine concentrations (means = 1,103 ng/ml) were reached between 1 and 8 hours after oral dosing (means = 4 hours). The mean relative bioavailability was 27.6% +/- 20%. Oral bioavailability was less than 10% in 17% of our subjects. The absorption and clearance of cyclosporine were highly variable. We conclude that the variability in the kinetics of cyclosporine makes trough blood level monitoring essential in the management of patients who receive renal transplants.

Effects of ibuprofen on the disposition kinetics of phenytoin in pregnant rats.

The effects of ibuprofen on maternal phenytoin pharmacokinetics and fetal phenytoin acquisition were investigated in 19-day gestation Sprague-Dawley rats. A 5 mg kg-1 bolus injection of 14C-phenytoin was given with and without (control) pretreatment with 12.5 mg kg-1 of ibuprofen. Maternal plasma and fetal whole body samples were obtained at various times after the phenytoin bolus and evaluated simultaneously using a three-compartment maternal-fetal model. Ibuprofen pretreatment increased the maternal plasma clearance of phenytoin about three-fold and the overall apparent volume of distribution almost four-fold. No changes in the volume of the maternal central compartment or terminal first-order disposition rate constant were observed. Additionally, the maternal-to-fetal clearance of phenytoin was not altered in the ibuprofen-treated rats. No differences in the apparent fetal volume of distribution or areas under the fetal phenytoin concentration-time curves were observed between the control and ibuprofen-treated rats. The results of this study were consistent with ibuprofen-induced alterations in organ and tissue blood perfusion and demonstrated that, while the maternal disposition kinetics of phenytoin were altered by sodium ibuprofen coadministration, the maternal changes did not affect the extent of fetal exposure to phenytoin.