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A PBPK model for benzo(A)pyrene in the rat
Poster Session PI:
Ciprofloxacin is a fluoroquinolone used for the treatment of respiratory To clarify aspects of the distribution kinetics of tract infections. ciprofloxacin into the rat lung. different methods have been employed, namely (I) in vitro, (2) single-pass perfused lung preparation, and (3) in
Regardless of the study, ciprofloxacin concentrations were determined by HPLC.
viva.
The
in virro binding to lung homogenate and isolated subcellular fractions were determined by equilibrium dialysis. These studies s;lowed that ciprofloxacin has greater affinity for subcellular fractions rhan for the homogenate.
The perfusion experiments were performed using Krebs-Henseleit bicarbonate medium containing 4.5 % albumin, delivered at a flow rate of 5 ml/min. Ciprofloxacin (2.5 pglml) was infused for 20 min with the effluent collected automatically during and after the infusion. The washout curves, characterized by fwo phases, were best described by a biexponential equation. A volume of distribution of oprofloxacin in lung of 7.34 * 5.18 ml/g. which was higher than the physiological value, implies rhat this compound has an affinity for lung tissue. The in viva studies were performed after intravenous bolus admimsiration (5 mg/kg). A flow-limited physiological pharmacokinetic model was developed aimed at predicting the kinetics of ciprofloxacin in lung. The early tissue concentrarion data deviated from those predicted by rhe model, whereas later data points (> 30 min) agreed with Ihe predicted values, suggesting that diffusion barriers and binding sites for ciprofloxacin exist in the lung. This was confirmed with the results from both in IWO and isolated perfused lung studies. Collectively. these data Indicate that ciprofloxacin distribution into the lungs is neither instantaneous nor homogeneous.
Physiologically-based pharmacokinetic (PBPK) models are useful for predicting organ-specific distribution of drugs and xenobiotics. With the use of these models, optimum dosages that yield drug concentrations remaining below toxic levels in normal tissues and at the desired level in tissues where therapeutic benefits are sought, can be determined. PBPK models are also used by regulatory agencies to improve health risk assessment for environmental chemicals. The objective of the present study was to develop a PBPK model of benzolajpyrene IBPI after intravenous (iv) administration in the rat. The PBPK model for BP is characterized by seven compartments: blood (b), fat (f), liver (I), kidney (k), lung (9). richly perfused tissues (rl and poorly perfused tissues (p). The tissue uptake of BP was described as a perfusionlimited process in some tissues. and as a diffusion-limited process in others. Of the parameters required for solving the BP PBPK model, the physiological parameters such as organ volumes and blood flow rates were obtained from the literature as were the maximal velocity for metabolism (Vmax, = 0.244, Vmax, = .0034 mglminlkg) and Michaelis affinity constant (Km, = 1.386, Km, = .0554 mg/L). Tissue to blood partition coefficients were obtained from membrane dialysis experiments {f:b = 7.78, I:b = 2.31, k:b = 2.08, g:b = 1.788, r:b = 1.277, p:b = 0.693). The differential equations constituting the BP PBPK model were solved using a commercially-available software IScoP). The mb;del predictions were compared with tissue and,blood time course concentration data obtained in rats administered 2, 6 or 15 mg BP/kg (iv). This PBPK model should be useful for predicting the tissue distribution and pharmacokinetics of BP in exposed organisms.
Sunday 15 September
Many drugs are given followmg “periodic” or “quasi-uniform” multlple doslng regimens (QUMDR). which are nonuniform wlthin a certain period. but repeated In the successive periods throughout the administratlon course. Slmllarly to the well studied uniform multiple dosing regimens (UMDR). such regimens also produce accumulation curves. converging to quasi steady state as hme progresses The purpose of this study is to derive estimates of the accumulation parameters (rate of accumulation, mean concentrahon at the plateau) dunng QUMDR. relahng them to those for UMDR. The denvahons are based on the superposition principle in linear pharmacokmet#cs UMDR are consldered as a special class of QUMDR with constant doses and Intervals within one period. Given a QUMDR, a “dose-equivalent” UMDR IS defined, having the same total periodic dose and number of dosing mtewals The followtng relations apply (0 both regimens have the same mean concentrahons at plateau, and (i,) if, at any time. the total administered dose for the QUMDR is greater or equal to that for the UMDR. the farmer has a greater or equal rate of accumulahon than the latter. Therefore, estimates of the accumulation rate and the plateau level&t& QUMDR from those of It’s -dose-equivalent” UMDR can be &t@d. They are further detailed for the most common types of QUMDR [with a constant dose or dosing interval) for a more precise estimation of the accumulahon parameters The proposed method 1s applied to two practically Important cases. (I) when destgning a dosage regimen for a drug in which the response IS related both to the plateau level and the rate of accumulation; and (in) when esttmahng the error of assuming a UMDR, while a QUMDR has been actually followed The results for the simulations fot the first case show, that if rapld onset of effect IS aimed at, but a “loading dose - maintenance dose” scheme IS lrrelevent due to accumulation rate limiting adverse effects, a sultable QUMDR can be an alternative. For the second case, it is shown that the error inflicted by the assumption violabon can be sigmficant. The present method can also be applied to the study of the accumulation profiles of metabolltes, prowded they follow llnear pharmacokmetics
The liver is one of the primary organs for elimination of compounds from the body. Within the liver, observed differences in drug elimination generally occur as result of a number of different physiological processes’ including organ perfusion, binding to blood components, enzymatic and cellular activity, and membrane permeability and in addition, possibly route of input- portal vein (PV) and hepatic artery (HA). The present study was therefore designed to examine heparic disposition of diazepam as a function of route of input. The in situ rat liver (n = 11) was perfused dually using Krebs Bicarbonate buffer containing various albumin concentrations (O-1 %) and unlabelled diazepam (1 mg I-‘) under constant HA (3 ml min.‘) and PV (12 ml min.‘) flow rates. Hepatic disposition of diazepam was investigated following an unit impulse (using “C-diazepam) and under steady state (using unlabelled diazepam) conditions. In the absence of albumin the hepatic availability of .diazepam following arterial infusion (0.046 f 0.013) was about twice that following venous infusionf$ 019 f 0.006). Also regardless of the route of input, the shape of the out ow profiles of “C-diazepam following bolus administration was dependent upon the albumin concentration: with a decrease in the albumin concentration from I 10 0.25% the early sharp peak (about 12-18 set) disappeared and the outflow curves displayed a flatter unimodal characteristic and a later peak (about 60-70 set). These results indicate that
route of input and albumin have a clear effect on the hepatic availability and disposition of diazepam. ’ Rowland M and Evans AM: In New Trends in Pharmacokinerics, PP 83
Plenum Press. 1991.
Ciprofloxacin is a fluoroquinolone used for the treatment of respiratory To clarify aspects of the distribution kinetics of tract infections. ciprofloxacin into the rat lung. different methods have been employed, namely (I) in vitro, (2) single-pass perfused lung preparation, and (3) in
Regardless of the study, ciprofloxacin concentrations were determined by HPLC.
viva.
The
in virro binding to lung homogenate and isolated subcellular fractions were determined by equilibrium dialysis. These studies s;lowed that ciprofloxacin has greater affinity for subcellular fractions rhan for the homogenate.
The perfusion experiments were performed using Krebs-Henseleit bicarbonate medium containing 4.5 % albumin, delivered at a flow rate of 5 ml/min. Ciprofloxacin (2.5 pglml) was infused for 20 min with the effluent collected automatically during and after the infusion. The washout curves, characterized by fwo phases, were best described by a biexponential equation. A volume of distribution of oprofloxacin in lung of 7.34 * 5.18 ml/g. which was higher than the physiological value, implies rhat this compound has an affinity for lung tissue. The in viva studies were performed after intravenous bolus admimsiration (5 mg/kg). A flow-limited physiological pharmacokinetic model was developed aimed at predicting the kinetics of ciprofloxacin in lung. The early tissue concentrarion data deviated from those predicted by rhe model, whereas later data points (> 30 min) agreed with Ihe predicted values, suggesting that diffusion barriers and binding sites for ciprofloxacin exist in the lung. This was confirmed with the results from both in IWO and isolated perfused lung studies. Collectively. these data Indicate that ciprofloxacin distribution into the lungs is neither instantaneous nor homogeneous.
Physiologically-based pharmacokinetic (PBPK) models are useful for predicting organ-specific distribution of drugs and xenobiotics. With the use of these models, optimum dosages that yield drug concentrations remaining below toxic levels in normal tissues and at the desired level in tissues where therapeutic benefits are sought, can be determined. PBPK models are also used by regulatory agencies to improve health risk assessment for environmental chemicals. The objective of the present study was to develop a PBPK model of benzolajpyrene IBPI after intravenous (iv) administration in the rat. The PBPK model for BP is characterized by seven compartments: blood (b), fat (f), liver (I), kidney (k), lung (9). richly perfused tissues (rl and poorly perfused tissues (p). The tissue uptake of BP was described as a perfusionlimited process in some tissues. and as a diffusion-limited process in others. Of the parameters required for solving the BP PBPK model, the physiological parameters such as organ volumes and blood flow rates were obtained from the literature as were the maximal velocity for metabolism (Vmax, = 0.244, Vmax, = .0034 mglminlkg) and Michaelis affinity constant (Km, = 1.386, Km, = .0554 mg/L). Tissue to blood partition coefficients were obtained from membrane dialysis experiments {f:b = 7.78, I:b = 2.31, k:b = 2.08, g:b = 1.788, r:b = 1.277, p:b = 0.693). The differential equations constituting the BP PBPK model were solved using a commercially-available software IScoP). The mb;del predictions were compared with tissue and,blood time course concentration data obtained in rats administered 2, 6 or 15 mg BP/kg (iv). This PBPK model should be useful for predicting the tissue distribution and pharmacokinetics of BP in exposed organisms.
Sunday 15 September
Many drugs are given followmg “periodic” or “quasi-uniform” multlple doslng regimens (QUMDR). which are nonuniform wlthin a certain period. but repeated In the successive periods throughout the administratlon course. Slmllarly to the well studied uniform multiple dosing regimens (UMDR). such regimens also produce accumulation curves. converging to quasi steady state as hme progresses The purpose of this study is to derive estimates of the accumulation parameters (rate of accumulation, mean concentrahon at the plateau) dunng QUMDR. relahng them to those for UMDR. The denvahons are based on the superposition principle in linear pharmacokmet#cs UMDR are consldered as a special class of QUMDR with constant doses and Intervals within one period. Given a QUMDR, a “dose-equivalent” UMDR IS defined, having the same total periodic dose and number of dosing mtewals The followtng relations apply (0 both regimens have the same mean concentrahons at plateau, and (i,) if, at any time. the total administered dose for the QUMDR is greater or equal to that for the UMDR. the farmer has a greater or equal rate of accumulahon than the latter. Therefore, estimates of the accumulation rate and the plateau level&t& QUMDR from those of It’s -dose-equivalent” UMDR can be &t@d. They are further detailed for the most common types of QUMDR [with a constant dose or dosing interval) for a more precise estimation of the accumulahon parameters The proposed method 1s applied to two practically Important cases. (I) when destgning a dosage regimen for a drug in which the response IS related both to the plateau level and the rate of accumulation; and (in) when esttmahng the error of assuming a UMDR, while a QUMDR has been actually followed The results for the simulations fot the first case show, that if rapld onset of effect IS aimed at, but a “loading dose - maintenance dose” scheme IS lrrelevent due to accumulation rate limiting adverse effects, a sultable QUMDR can be an alternative. For the second case, it is shown that the error inflicted by the assumption violabon can be sigmficant. The present method can also be applied to the study of the accumulation profiles of metabolltes, prowded they follow llnear pharmacokmetics
The liver is one of the primary organs for elimination of compounds from the body. Within the liver, observed differences in drug elimination generally occur as result of a number of different physiological processes’ including organ perfusion, binding to blood components, enzymatic and cellular activity, and membrane permeability and in addition, possibly route of input- portal vein (PV) and hepatic artery (HA). The present study was therefore designed to examine heparic disposition of diazepam as a function of route of input. The in situ rat liver (n = 11) was perfused dually using Krebs Bicarbonate buffer containing various albumin concentrations (O-1 %) and unlabelled diazepam (1 mg I-‘) under constant HA (3 ml min.‘) and PV (12 ml min.‘) flow rates. Hepatic disposition of diazepam was investigated following an unit impulse (using “C-diazepam) and under steady state (using unlabelled diazepam) conditions. In the absence of albumin the hepatic availability of .diazepam following arterial infusion (0.046 f 0.013) was about twice that following venous infusionf$ 019 f 0.006). Also regardless of the route of input, the shape of the out ow profiles of “C-diazepam following bolus administration was dependent upon the albumin concentration: with a decrease in the albumin concentration from I 10 0.25% the early sharp peak (about 12-18 set) disappeared and the outflow curves displayed a flatter unimodal characteristic and a later peak (about 60-70 set). These results indicate that
route of input and albumin have a clear effect on the hepatic availability and disposition of diazepam. ’ Rowland M and Evans AM: In New Trends in Pharmacokinerics, PP 83
Plenum Press. 1991.