Search

Purpose In order to clarify the effect of rifampicin on the bioavailability of the P-glycoprotein substrate talinolol, its absorption kinetics was modeled after multiple-dose oral administration of talinolol in healthy subjects. Methods A sum of two inverse Gaussian functions was used to calculate the time course of the input rate into the systemic circulation. Results The estimated rate of drug entry into the systemic circulation revealed two distinct peaks at 1 and 3.5 h after administration. Rifampicin did not affect bioavailability of talinolol, but did shift the second peak of the input function by 1.3 h to later times. Elimination clearance and one of the intercompartmental distribution clearances increased significantly under rifampicin treatment. Conclusions Rifampicin changes the time course of absorption rate but not the fraction absorbed of talinolol. The model suggests the existence of two intestinal absorption windows for talinolol.

Purpose To develop a semi-distributed liver model for the evaluation of saturable sinusoidal uptake and binding kinetics of the Oatp1a4 substrate digoxin. Methods In the perfused rat liver, two successive digoxin doses of 42 and 125 µg were administered, and the outflow concentration was determined by LC/MS/MS. [14C]-sucrose was used as vascular reference. The data were analyzed simultaneously by a population approach using sucrose to determine the sinusoidal mixing of digoxin. Results The results suggest the existence of a high-affinity, low-capacity system, and a low-affinity, high-capacity system for sinusoidal uptake with apparent Michaelis constants (K M) of 0.24 and 332 µg/ml, respectively. Incorporation of saturable sinusoidal binding of digoxin considerably improved the fit, and the parameter estimates were consistent with those of binding to hepatic Na,K-ATPase. Simpler models that neglect the concentration gradient in flow direction failed to describe the outflow data in the high dose range. Conclusion The semi-distributed liver model with saturable uptake should be useful for a functional characterization of transporters in the in situ rat liver. Refereed/Peer-reviewed

To evaluate distribution kinetics of drugs by the relative dispersion of disposition residence time and demonstrate its uses, interpretation and limitations.The relative dispersion was estimated from drug disposition data of inulin and digoxin fitted by three-exponential functions, and calculated from compartmental parameters published for fentanyl and alfentanil. An interpretation is given in terms of a lumped organs model and the distributional equilibration process in a noneliminating system.As a measure of the deviation from mono-exponential disposition (one-compartment behavior), the relative dispersion provides information on the distribution kinetics of drugs, i.e., diffusion-limited distribution or slow tissue binding, without assuming a specific structural model. It also defines the total distribution clearance which has a clear physical meaning.The residence time dispersion is a model-independent measure that can be used to characterize the distribution kinetics of drugs and to reveal the influence of disease states. It can be estimated with high precision from drug disposition data.

To determine the effect of the P-glycoprotein (Pgp) modulator amiodarone on the pharmacokinetics and pharmacodynamics (PK/PD) of Pgp substrate verapamil in the perfused rat heart. In Langendorff-perfused rat hearts, the outflow concentration–time curve and inotropic response data were measured after a 1.5 nmol dose of [3H]-verapamil (infused within 1 min) in the absence and presence of the amiodarone (1 μM) in perfusate, as well as using a double dosing regimen (0.75 nmol in a 10 min interval). These data were analyzed by a PK/PD model. Amiodarone failed to influence the rapid uptake and equilibrium partitioning of verapamil into the heart. The time course of the negative inotropic effect of verapamil, including the ‘rebound’ above the original baseline after the infusion of verapamil was stopped, could be described by a PK/PD tolerance model. Tolerance development (mean delay time, 12 min) led to a reduction in predicted steady-state effect (16%). The EC50 and E max values as estimated in single dose experiments were 16.4 ± 4.1 nM and 50.5 ± 18.9 mmHg, respectively. The result does not support the hypothesis that Pgp inhibition by amiodarone increases cardiac uptake of the Pgp substrate verapamil.

The purpose of this study was to construct a mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model for digoxin that describes the relationship between plasma concentration and inotropic response.On the basis of results obtained in the isolated perfused rat heart, a PK/PD model for digoxin in humans was developed. In fitting the model to previously published bolus dose and concentration clamp data (shortening of electromechanical systole), the plasma concentration-time curves were used as forcing functions in the computer program ADAPT II.The mechanistic approach allowed a modeling of digoxin pharmacodynamics which is consistent with available inotropic response data. The estimates of the receptor binding parameters were in the same order of magnitude as those measured in vitro for ouabain. The mechanistic model explained the parameters of the empirical link model (EC50, Emax and delay time tau) in terms of the underlying processes, suggesting that the long equilibration half-time of 13 h is due to slow receptor binding. The empirical link model, in contrast, is not compatible with a noninstantaneous receptor binding process and led to estimates of the delay time tau that were dependent on the digoxin administration schedule.The new, mechanistic model may provide a rationale for better understanding of digoxin pharmacodynamics and could become a tool to bridge the gap between in vitro and in vivo studies.

Purpose. Little is known of how anthracyclines are transported into the heart. Our previous kinetic study suggested saturable myocardial uptake of idarubicin. This study sought to determine the effects of temperature reduction and of doxorubicin coadministration on the transport process. Methods. In Langendorff-perfused rat hearts, a 0.5 mg dose of idarubicin was infused over 10 min. The outflow concentration-time curve as well as the residual amounts in cardiac tissue of idarubicin and its active metabolite idarubicinol were measured after temperature reduction (from 37°C to 30°C) and in the presence of doxorubicin (20 μM) in the perfusate. The outflow concentration-time profile of idarubicin was analyzed by a four-compartment model and simultaneous nonlinear regression. Results. Doxorubicin significantly inhibited the Michaelis-Menten-like uptake process of idarubicin in the heart (50% decrease in V max), leading to a decreased net tissue uptake of idarubicin. Kinetic analysis of sensitivity to temperature reduction revealed a 2.6-fold increase in K M; however, this inhibition of idarubicin uptake was counterbalanced by a decrease in efflux rate. Conclusions. These data confirm the existence of a saturable myocardial uptake mechanism for idarubicin and might provide useful information for optimizing anthracycline dosage regiments.

Purpose. To investigate new models characterizing dissolution data obtained for heterogenous materials (model I) and under randomly time-varying conditions (model II).

Purpose. The clinical utility of anthracyclines like idarubicin (IDA) is limited by the occurrence of multidrug resistance and cardiotoxicity. Previous studies have demonstrated that the multidrug transporter P-glycoprotein (P-gp) is present in the heart and have suggested that it exerts a protective function. We sought to determine the influence of P-gp inhibitors verapamil and PSC 833 on myocardial uptake, metabolism, and actions of IDA.

Purpose. To develop a viable, single pass rat head perfusion modeluseful for pharmacokinetic studies.

Purpose. The sensitivity and effectiveness of indirect metrics proposedfor the assessment of comparative absorption rates in bioequivalencestudies [Cmax, Tmax, partial AUC(AUCp), feathered slope (SLf), interceptmetric (I)] were originally tested by assuming first-order absorption.The present study re-evaluates their sensitivity performances using themore realistic inverse Gaussian (IG) model characterizing the inputprocess for oral drug administration.

Purpose. To present a new model for describing drug dissolution. On the basis of the new model to characterize the dissolution profile by the distribution function of the random dissolution time of a drug molecule, which generalizes the classical first order model.

Little is known of how anthracyclines are transported into the heart. Our previous kinetic study suggested saturable myocardial uptake of idarubicin. This study sought to determine the effects of temperature reduction and of doxorubicin coadministration on the transport process.In Langendorff-perfused rat hearts, a 0.5 mg dose of idarubicin was infused over 10 min. The outflow concentration-time curve as well as the residual amounts in cardiac tissue of idarubicin and its active metabolite idarubicinol were measured after temperature reduction (from 37 degrees C to 30 degrees C) and in the presence of doxorubicin (20 microM) in the perfusate. The outflow concentration-time profile of idarubicin was analyzed by a four-compartment model and simultaneous nonlinear regression.Doxorubicin significantly inhibited the Michaelis-Menten-like uptake process of idarubicin in the heart (50% decrease in Vmax), leading to a decreased net tissue uptake of idarubicin. Kinetic analysis of sensitivity to temperature reduction revealed a 2.6-fold increase in KM; however, this inhibition of idarubicin uptake was counterbalanced by a decrease in efflux rate.These data confirm the existence of a saturable myocardial uptake mechanism for idarubicin and might provide useful information for optimizing anthracycline dosage regiments.