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BMC Clinical Pharmacology 2003 3 http www biomedcentral com 1472 6904 3 3. reviews of the structure and function of the interstitial Measurement of steady state volume of distribution Vss. space 2 3 To ensure that a consistent calculation of Vss was used all. the values of Vss were recalculated by applying PKQuest. An accurate pharmacokinetic description of the interstitial 8 to the published venous concentration data In this. space is essential for the development of a physiologically calculation deconvolution of the intravenous input is. based pharmacokinetic model PBPK for extracellular used to find the 2 or 3 exponential unit dose bolus. solutes Although PBPK models have been used exten response function r t. sively to describe human pharmacokinetics nearly all of. these studies have involved solutes that have intracellular P. distributions and thus do not require detailed modeling 1 r t Bi e t Ti. of the interstitial space One exception is the recent appli i 1. cation of PKQuest to the extracellular solutes inulin and The expression for Vss is then found from the area under. the beta lactam antibiotics 4 PKQuest is a new PBPK the curve AUC and mean residence time MRT for this. program that has been applied to the human pharmacok r t for unit dose. inetics of a large number of solutes 4 8 Although the. agreement between the PKQuest PBPK model predictions P P. and the experimental data for these extracellular solutes 2 Vss MRT AUC Bi Ti2 Bi T 2. was satisfactory subsequent application of PKQuest to i 1 i 1. other extracellular solutes demonstrated that there was a Measurement of equilibrium volume of distribution Veq. small but systematic error in the PKQuest predictions The direct approach to the determination of Veq is to give. This error is the stimulus for this more in depth analysis a constant IV infusion for a period long enough to estab. of interstitial pharmacokinetics lish a steady state plasma concentration Ceq For solutes. in which the systemic clearance results only from renal. Probably the most detailed application of a PBPK model clearance the peripheral tissue and central concentra. to an extracellular solute is the study of Tsuji et al 9 of tions must be in equilibrium at this steady state and Veq is. the pharmacokinetics of cefazolin in the rat In this inves defined by. tigation nearly every PBPK parameter required by the. model was directly measured including organ blood 3 Veq Atot Ceq. flows and weights renal and hepatic clearance and the. time dependence of cefazolin concentration in the differ where Atot is the total amount of solute present For the. ent organs Tsuji et al 9 estimated interstitial volumes special case where there is no metabolism and renal clear. from measurements of the steady state inulin tissue con ance in the only excretion route Atot can be determined by. centrations The interstitial volumes in the original quantitative urine collection after stopping the infusion If. PKQuest PBPK model were based on these inulin volumes the clearance is from just the central compartment e g. of Tsuji et al 9 scaled to give the correct total volume in renal excretion Veq also referred to as Vdrug is equal to Vss. humans As will be shown below inulin is not a good sol 10. ute to use to measure interstitial volume and this probably. contributed to the error in the earlier PKQuest PBPK The value of Veq can also be estimated for subjects in renal. predictions failure that have a very low rate of renal clearance As. shown in Appendix I for the case where the clearance is. Methods very small compared to the rate of exchange between com. All the experimental data were obtained from earlier pub partments Veq is approximately equal to Vdext using the. lications In most cases the published data represented notation of Wagner 11. the average of the experimental measurements in a, number of subjects and it was assumed that it represented 4 Veq Vdext D B. one average subject In a few cases indicated by a N 1. in Table data for a single subject were published and where B is the coefficient of the slow terminal exponen. used in the calculations The program UN SCAN IT Silk tial term of the bolus response function eq 1 and D is. Scientific Corporation was used to read the data from the the bolus dose The value of B was determined using the. published figures Most of the figures shown in this paper deconvolution feature in PKQuest to find the 2 exponen. are direct copies in jpeg format of standard PKQuest tial response function. PBPK model for extracellular solutes, A new PBPK model was developed that was consistent. with the experimental data in Tables 1 2 3 4 5 Table 6. Page 2 of 29,page number not for citation purposes. BMC Clinical Pharmacology 2003 3 http www biomedcentral com 1472 6904 3 3. Table 1 Steady state Volume of Distribution relative to body weight VSS and total body water VSSW for selected solutes. Solute Reference Fraction Bound VSS liters Kg VSSW liters liter Comments. 2 expon 3 expon,Mannitol 58 0 28 48 N 7 28 years 70 9 Kg 178 cm. EDTA 0 265 45,Mannitol 57 0 33 33 56 N 1 71 6 Kg 172 cm.
amoxicillin 62 17 23 262 275 44 N 9 66 4 Kg,61 267 253 45 N 9 74 7 Kg 180 cm. morphine 6 glucuronide 59 0 1 247 245 42 N 20 74 2 Kg. 42 30 40 50 N 10 71 Kg,morphine 3 glucuronide 60 275 273 47 N 3 Dose Kg. inulin 37 0 133 131 22 N 1 87 3 Kg 173 cm,39 0 131 136 23 N 1 77 1 Kg 186 cm. 40 0 20 277 34 N 27 Non linear, Table 2 Equilibrium Volume of Distribution in Humans relative to body weight VEQ for selected solutes. Solute Reference Fast time constant Slow time constant VEQ liters Kg Comments. minutes minutes, Amoxicillin 46 9 8 909 0 26 N 4 53 Kg 45 years Renal failure.
Clearance 10 ml min 1 73 m2, Morphine 6 glucuronide 47 23 2083 0 24 N 6 73 7 Kg 48 7 years Renal. Failure Ave clearance 10 ml min,Inulin 44 NA NA 0 15 N 3 Constant infusion Normal. Males ages 21 29,Sucrose 45 NA NA 0 159 N 3 Constant infusion. Inulin NA NA 0 162, Table 3 Steady state volume of distribution VSS and interstitial volume VI relative to body weight for lactam antibiotics as a. function of degree of protein binding, Solute Reference Fraction Bound VSS liters Kg VI liters Kg.
amoxicillin 62 17 23 26 22,piperacillin 30 48 23 19. cefatrizine 31 62 194 155,ceforanide 32 82 161 12,dicloxacilllin 63 97 091 053. amoxicillin 29 17 23 33 29,flucloxacillin 93 15 11. summarizes the new set of PBPK parameters for the different organs The column labeled ecf fract is the frac. standardhuman with a total weight of 70 Kg and a 20 tion of the extravascular organ water that is extracellular. fat content The parameters are scaled for different body i e interstitial The adipose ecf fract is 1 because it is. weight and fat content 7 The major difference between assumed that all adipose tissue water is extracellular and. this parameter set and that used previously 7 is the dis the cells are pure lipid The brain ecf fract is zero because. tribution of the extracellular water ecf water among the the blood brain barrier will prevent the distribution into. Page 3 of 29,page number not for citation purposes. BMC Clinical Pharmacology 2003 3 http www biomedcentral com 1472 6904 3 3. the interstitial space of any of the test solutes used in Table cardiac output of 5 62 L min is close to the value of 5 82. 1 The term solid refers to the non fat organ solids It is L min in normal young men reported by Grimby et al. assumed that the entire animal s fat is in the single lipid 24. organ and that this organ is 80 fat This is a major over. simplification since adipose blood flow may show large The volume of distribution in the different organs for sol. variations in different adipose tissues 12 and two differ utes that bind to albumin is characterized by the parame. ent fat compartments have been used in some PBPK ter KAi the ratio of the albumin concentration in the EDTA. models 13 An attempt has been made to minimize the interstitial space to the plasma albumin concentration for. number of adjustable parameters and a single fat com organ i see Appendix II and III The PBPK values of KAi. partment has provided satisfactory fits to the solutes pre for the different organs are listed in Table 6 In the analysis. viously investigated with PKQuest including the highly of the pharmacokinetics of the protein bound lactam. fat soluble volatile anesthetics 5 Portal refers to the antibiotics an average value of KA see eq 10 for the. organs drained by the portal vein stomach small and entire human is estimated This corresponds to the organ. large intestine pancreas and spleen Bone refers to the weighted sum. inert solid component of bone that has no volume of dis. tribution or blood flow The blood flow and water com. ponent of the skeleton is distributed among the rest of the 5 K A ecfi K iA ecfi. organs i i, The organ weights in Table 6 are close to the values in the where ecfi is the interstitial volume of organ i The PBPK.
Report on the Task Group on Reference Man 12 The organ weighted values are listed in the last column of. skin is the sum of the weight of the dermis and epider Table 6 and correspond to an average value of KA of 4 94. mis The organ other represents primarily the loose con 17 45 0 28 This is identical to the value that was esti. nective tissue and the organ tendon represents the mated using the lactam antibiotics see fig 15. denser connective tissue components The total body. water is 41 84 liters in agreement with the results of As described previously 4 capillary permeability limited. Chumlea et al 14 It is assumed in Table 6 that the solutes are characterized by the organ parameter fclear i. blood volume includes the intra organ blood volume the fraction of solute that equilibrates with the tissue in. so that the organ parameters refer to the extravascular one pass through the capillary The fclear of organ i is. composition related to the capillary permeability surface area product. PSi by the relation, Although the blood flows to the different organs in Table. 6 are in general agreement with the proposed reference 6 fclear i 1 exp fPPSi Fi. values of Williams and Leggett 15 they have been fine. tuned in order to optimize the PBPK model predictions where fP is the fraction free in the plasma and Fi is the. for selected solutes The resting muscle blood flow was organ plasma volume flow liters min Kg 7 The. adjusted to a value of 2 25 ml min 100 g 0 0225 L Kg parameter fclear ranges from 0 impermeable capillary to. min to fit the D2O data of Schloerb et al 16 as 1 flow limited In PKQuest the default procedure is to. described previously 6 This value for muscle blood flow input just one parameter the fclear muscle and the per. is similar to the recent measurements in man of resting meability of all the other organs are then automatically. muscle blood flow of 2 3 17 and 3 12 ml min 100 gm determined using the default values of PSi PSmuscle pro. Ruotsalainen 239 using 15O H2O PET scans and of grammed into PKQuest This accounts for the other phys. 2 5 ml min 100 gm 18 using plethysmographic meas iological factors that determine fclear organ plasma flow. urements of calf blood flow This value is somewhat and plasma protein binding The following set of default. higher then 133Xe measurements which vary from 1 4 to PS values are assumed liver kidney and portal organs are. 1 9 ml min 100 gm 19 Similarly the adipose blood flow limited heart and lung have a PS 50 times that of. flow in Table 6 was adjusted 5 to a value of 4 4 ml min skeletal muscle brain has a PS 0 for solutes that have. 100 gm to fit the enflurane data of Munson et al 20 fclear muscle 1 due to the blood brain barrier and the. This value is close to the recent human 15O H2O meas rest of the organs have a PS equal to that of muscle 25. urements of subcutaneous abdominal 4 8 ml min 100 As can be seen from eq 6 solutes that have a high. gm visceral 5 9 and perirenal 4 9 fat blood flow 21 intrinsic capillary permeability PS can have a functional. The tendon e g connective tissue blood flow is poorly capillary permeability limitation fclear 1 if there is a. characterized and has a large variation The value of 1 ml high degree of plasma protein binding i e fP is small. 100 gm min is representative of direct measurements of This dependence of fclear on protein binding is applied. tendon blood flow using microspheres 22 23 The total. Page 4 of 29,page number not for citation purposes. BMC Clinical Pharmacology 2003 3 http www biomedcentral com 1472 6904 3 3. Table 4 Interstitial volume VI fraction of total extravascular water. Species Solute Reference Organ VI Comments, Rat EDTA 35 64 65 sk mus 081 091 Renal ligature sampled 30 minutes after. skin 55 73,intestine 28 32,66 sk mus 12 Renal ligature samples from live rat. 67 1 sk mus 075 Constant infusion Measured time course of. tissue uptake, intestine 15 25 Muscle stomach and intestine equilibrated in.
40 minutes,stomach 23,adipose 49, 50 skin 61 Renal ligature divided skin into dermis and. sub cutaneous samples,subcutis 51, 68 1 sk mus 15 Constant infusion Volume increased with. time for skin and colon Range indicates,volume at 60 to 120 minutes. skin 44 63,sm intestine 29,colon 3 41,adipose 1 0,Sulfate 69 1 skin 65 Nephrectomized. Mannitol skin 66,Sulfate 70 1 2 muscle 12 Nephrectomized.
Inulin 9 sk mus 12 Constant infusion,intestine 12,71 1 sk mus 1 Constant infusion Tissue uptake. corresponds to capillary PS 0 6 ml min 100,Rabbit EDTA 72 sk mus 077 Renal ligature. EDTA 73 1 2 sk mus 10 Renal ligature Measured time course of. tissue uptake,Sucrose sk mus 11 Equilibrated in 30 minutes. Inulin sk mus 1, 74 sk mus 09 Renal ligature Determined time constant T. heart 28 T 1 min,intestine 2 T 1 5 min,ear 5 T 12 min.
Cat EDTA 75 sk mus 13 Renal ligature,Dog EDTA 76 sk mus 16 Renal ligature. Page 5 of 29,page number not for citation purposes. BMC Clinical Pharmacology 2003 3 http www biomedcentral com 1472 6904 3 3. Table 4 Interstitial volume VI fraction of total extravascular water Continued. Sulfate 70 1 2 muscle 20 Constant infusion Equilibration time 30. Sucrose 49 1 sk mus 23 Constant infusion Cannulated prepopliteal. lymphatic and measured lymph sucrose, Thiosulfate 51 2 muscle 13 Renal ligature Equilibration time 180 min. skin 77 Equilibration time 180 min,tendon 75 Equilibration time 360 min. Inulin muscle 1 Equilibration time 180 min,skin 48 Equilibration time 180 min.
tendon 26 Equilibration time 360 min, Man Inulin1 2 77 sk mus 08 11 Bolus plus constant infusion Tissue biopsy. after 20 120 minutes, 1Assumed total organ water ml 100 gm of skeletal muscle 75 heart 78 skin 60 subcutaneous tendon ear 60 stomach 75 intestine 73. adipose 18 3 liver 70 lung 79 35 78 2Assumed plasma volume ml 100 gm of skeletal muscle 0 4 heart muscle 2 0 skin 0 6 64 78. Table 5 Interstitial albumin volume as fraction of interstitial EDTA volume VIA VIE the interstitial albumin concentration relative to. plasma albumin CI CP and the product KA VIA VIE CI CP. Species Reference Organ CI CP VIA VIE KA Comments, Rat 64 sk mus 0 8 0 73 0 58 Constant infusion of I125 rat. serum albumin Wick tissue,skin 0 69 0 6 0 4,tendon 0 61 0 45 0 27. 50 skin dermis 0 72 0 44 0 32,skin subcut 0 72 0 57 0 41.
Rabbit 79 sk mus 0 76 0 53 0 4 Lymph albumin,skin 0 49 0 47 0 23. Table 6 Spreadsheat description of PBPK parameters for the 70 Kg 20 fat standardhuman. Organ Weight Lipid Solid Solid ecf water water Kg ecf flow L Kg flow L min Ka Ka ecf. Kg Fraction Fraction Kg Fraction L water L,Blood 5 5 0 0 18 0 99 0 595 4 51 0 82 2 68345. liver 1 8 0 0 3 0 54 0 23 1 26 0 7 0 2898 0 25 0 45 0 5 0 1449. portal 1 5 0 0 22 0 33 0 3 1 17 0 78 0 351 0 75 1 125 0 35 0 1228. muscle 26 0 0 22 5 72 0 15 20 28 0 78 3 042 0 0225 0 585 0 5 1 521. kidney 0 31 0 0 2 0 062 0 165 0 248 0 8 0 04092 4 1 24 0 35 0 0143. brain 1 4 0 0 2 0 28 0 1 12 0 8 0 0 56 0 784 0 1 0. heart 0 33 0 0 2 0 066 0 25 0 264 0 8 0 066 0 8 0 264 0 5 0 033. lung 0 536 0 0 2 0 107 0 2 0 428 0 8 0 08576 10 482 5 6184 0 35 0 03. skin 2 6 0 0 3 0 78 0 6 1 82 0 7 1 092 0 1 0 26 0 25 0 273. tendon 3 0 0 15 0 45 1 2 55 0 85 2 55 0 01 0 03 0 25 0 6375. other 5 524 0 0 15 0 828 0 8 4 695 0 85 3 75632 0 02 0 1104 0 25 0 9390. bone 4 0 1 4 0 5 0 0 0 0 0 0, adipose 17 5 0 8 0 0 1 3 5 0 2 3 5 0 044 0 77 0 35 1 225. Total 70 0 2 14 15 41 84 17 4572 5 6184 4 9406,Page 6 of 29. page number not for citation purposes, BMC Clinical Pharmacology 2003 3 http www biomedcentral com 1472 6904 3 3.
below in the application of PKQuest to a series of centrations in antecubital venous blood which differs. lactam antibiotics with varying protein binding from the arterial concentration due to the exchange with. the tissues drained by the antecubital vein A new feature. All the PBPK calculations use PKQuest 7 A small modi has been added to PKQuest that allows one to directly cor. fication of the earlier version of the software is required to rect for this effect in the PBPK model fitting The tissue. account for the new situation where the interstitial vol flow distribution supplying the antecubital vein was. ume of distribution of protein is less than that of EDTA established by applying PKQuest to the experimental data. see Appendix III Four parameters characterize the inter for a number of solutes for which simultaneous arterial. stitial volume of distribution for each organ i 1 ecf i and antecubital vein concentrations are available Levitt. the interstitial volume of EDTA as the fraction of the total in preparation This analysis indicated that antecubital. organ water 2 mecf a multiplicative constant that vein blood represents approximately 10 muscle 20. scales all the values of ecf i 3 frecf i interstitial vol skin 5 other 5 adipose and the rest 60 A V. ume of the solute relative to that of EDTA and 4 for sol anastomoses In PKQuest specifying arm as the sample. utes that are protein bound cProt i which is the site outputs the antecubital vein concentration and uses. PKQuest parameter corresponding to KAi Standard values this concentration to optimize the PBPK parameters using. of ecf Table 6 frecf 1 and cProt KAi Table 6 are pre the PKQuest minimization routines 7 This allows one. programmed in PKQuest The only parameter that needs to use antecubital vein blood samples when adjusting. to be input by the user is mecf Setting mecf 1 indicates PBPK parameters for an arbitrary uncharacterized solute. that the solute distributes in the standard ecf space The. default value of mecf is 1 indicating that the solutes dis Figure 1 shows the results of this analysis for two of the. tributes in all the tissue interstitial and intracellular extracellular solutes DTPA and inulin that were investi. space The complete PBPK pharmacokinetics of each sol gated to determine the organ composition of antecubital. ute is characterized by a short Maple worksheet that lists blood The squares show the experimental measurements. the parameters that differ from the default standardhu of the 99Tcm DTPA left column and inulin right col. man parameters The complete worksheets for the 11 sol umn sampled simultaneously from the artery black. utes are included in the additional file and antecubital vein red after a bolus venous input The. PKQuest worksheets doc For all of the solutes investi lines show the PBPK model fits for the arterial black and. gated in this paper the kidney is the major excretion path antecubital vein red concentrations The difference. way The renal clearance is described two different ways in between the arterial and antecubital vein concentrations. these worksheets If the clearance is close to the free become negligible after the first 5 to 10 minutes because. plasma glomerular clearance than the parameter rclr the antecubital vein blood is supplied primarily by high. glomerular filtration rate is used For solutes that are blood flow skin and A V anastomoses in the hand 26. cleared both by glomerular filtration and tubular secre For the solutes investigated in this paper the differences. tion the single parameter Tclr kidney is used the rate of between arterial and antecubital vein concentration are. renal clearance of the free unbound plasma solute very small e g see fig 2 and this correction is of minor. importance It is fortunate that this is the case Otherwise. PKQuest is used to find the values of the adjustable one could not use antecubital vein data for PBPK mode. parameters that provide the best fit to the experimental ling Unless otherwise stated all the PBPK model data. data by minimizing the error function shown in the figures in this paper correspond to antecu. bital vein blood,modeli datai, 7 Error Function Chiou 27 has emphasized that the measurement of the. i datai noise, steady state volume of distribution Vss using eq 2 is. The parameter noise adds a weighting factor that dependent on the sampling site and has shown that the. reduces the contribution of the low concentration data value of Vss determined using antecubital vein blood will. points The default value for noise is 10 of the average be greater than the true value of Vss using arterial blood. concentration Optionally PKQuest allows the choice of This effect can be quantitated for the extracellular solutes. a mean square error term and an arbitrary noise can be investigated in this paper using the experimental or PBPK. input model data shown in figure 1 Using this data the value. of Vss for the antecubital sampling site is from 4 PBPK. Correction for antecubital vein sampling model to 10 experimental data greater than the true. Ideally one would like to be able to sample arterial blood arterial Vss The values of Vss reported below are for the. for the calculations of steady state volume of distribution antecubital vein data A small correction will be applied. and for PBPK model fitting However all of the data used when these results are used to estimate the true extracellu. in this paper was obtained by measuring the plasma con lar volumes. Page 7 of 29,page number not for citation purposes. BMC Clinical Pharmacology 2003 3 http www biomedcentral com 1472 6904 3 3. DTPA Inulin,Arterial 1 black,andexperimental,antecubital vein. squares of Cousinsofet 99Tc,concentrations al m 56.
DTPA right column and inulin left column after a bolus. Arterial black and antecubital vein red concentrations of 99Tcm DTPA right column and inulin left column after a bolus. injection using the experimental data squares of Cousins et al 56 The solid lines indicate the PBPK model predictions for. the arterial black and antecubital vein red concentrations The top row shows a plot of the absolute concentration and the. bottom row is a semi log plot of the same data The PBPK parameters for DTPA were identical to those used for EDTA see. Page 8 of 29,page number not for citation purposes. BMC Clinical Pharmacology 2003 3 http www biomedcentral com 1472 6904 3 3. Figure 2 of PBPK model predictions and experimental data for mannitol plotted using linear left or semi log right. Comparison, Comparison of PBPK model predictions and experimental data for mannitol plotted using linear left or semi log right The. predictions for the experimental data of Laker et al 57 top and Elia et al 58 bottom are shown using the parameters in. Table 6 Both the model arterial black and antecubital vein red concentration curves are shown. Page 9 of 29,page number not for citation purposes. BMC Clinical Pharmacology 2003 3 http www biomedcentral com 1472 6904 3 3. Results resulting presumably from varying concentrations of. Experimental measurements of whole animal and collagen and hyaluronan in the different tissues The sixth. individual organ volumes of distribution for extracellular column is the product of these two ratios. Table 1 summarizes the experimental measurements in K iA CI CP VIA VIE CI VIA VIE CP. humans of the steady state volume of distribution Vss for 9. mannitol EDTA amoxicillin morphine 3 glucuronide Albumin concentration in EDTA space CP. morphine 6 glucuronide and inulin The volume of distri This product for organ i which will be referred to as KAi is. bution is expressed in terms of total body weight Vss lit the relevant parameter determining the pharmacokinetics. ers Kg and total body water Vssw liters liters The latter of albumin bound solutes such as the lactam antibiot. calculation was based on an assumption of a value of 41 ics see Appendix II. liters of water for the standard 70 Kg man with 20 body. fat 14 The total body water was adjusted for body fat PBPK model for extracellular solutes. estimates if information was available Table 2 lists the The PKQuest PBPK model 7 was applied to the extracel. values of the equilibrium volume of distribution Veq for lular solutes using the new set of parameters Table 6 A. amoxicillin morphine 6 glucuronide sucrose and inulin comparison of the model predictions with the experimen. see Methods Table 3 lists the Vss and the interstitial vol tal data is shown in figs 2 3 4 5 for mannitol EDTA mor. ume VI for a series of lactam antibiotics with varying phine 6 glucuronide and morphine 3 glucuronide. amounts of plasma protein binding VI was estimated by solutes with low or negligible protein binding Since one. subtracting a plasma water volume of 2 68 liters 70 Kg of the purposes of this analysis is to find a single unique. from Vss The human serum protein binding values used PBPK model applicable to all extracellular solutes the. in Tables 1 2 3 were from the following references amox identical set of PBPK parameters has been used in all these. icillin 28 29 piperacillin 30 cefatrizine 31 cefora figures The only parameter that was varied for each solute. nide 32 dicloxacillin 33 flucloxacillin 29 33 is the renal clearance determined using the optimization. morphine 3 glucuronide and morphine 6 glucoronide feature in PKQuest see Methods Figure 2 shows the. 34 Table 4 lists the interstitial volume as a fraction of PBPK model predictions for both the arterial and antecu. total extravascular organ water for selected solutes in rats bital vein concentration see Methods It can be seen that. rabbits cats dogs and man the difference is small In all other figures only the. antecubital vein concentration is shown, The solutes listed in Table 4 have a rapid possibly flow. limited exchange between the blood and interstitial space All of the solutes shown in figs 2 3 4 5 have been. so that the interstitial space equilibrates with the blood In assumed to be flow limited This is clearly not the case for. contrast albumin has a very slow rate of tissue plasma inulin which is the prototypical capillary permeability. exchange with a time constant of about 100 hours in the limited solute In addition the interstitial volume of dis. rat 35 Because of this low permeability the steady state tribution of inulin VI is clearly significantly smaller than. interstitial albumin concentration in a given tissue CI is that of EDTA Table 1 In PKQuest the parameter mecf. less than the plasma concentration and is determined by scales the interstitial volume of all non blood organs by. the balance between the rate of trans capillary exchange the same amount Thus for inulin there are 3 adjustable. and the rate of removal by lymph flow 36 The standard parameters 1 the renal clearance rclr 2 the intersti. procedure used to measure this concentration CI is to sam tial volume relative to that for EDTA mecf and 3 the. ple the lymph draining that tissue or to use the wick capillary permeability for muscle fclear muscle. method to sample the free tissue albumin The interstitial which sets the permeability for all the other organs see. albumin volume of distribution VIA for that tissue is then Methods The parameter fclear indicates the fraction of. defined by the solute that equilibrates with the tissue in one pass. through the capillary The flow limited case corresponds. 8 VIA Total Extravascular Albumin CI to an fclear equal to 1 Figure 8 shows the PBPK model. results for four different sets of experimental inulin data. The fourth column in Table 5 lists the steady state albu The values of mecf 0 42 and fclear muscle 0 409. min tissue plasma concentration ratios CI CP and the corresponding to PSmuscle 0 61 ml min 100 g see eq. fifth column lists the corresponding ratio VIA VIE where 6 were first determined by optimizing the fit to the data. VIE is the interstitial volume of EDTA for skeletal muscle of Odeh et al 37 top row fig 6 A good fit average. skin and tendon VIA is less than VIE because the interstitial error less than 2 was obtained with the 3 adjustable. matrix behaves like a size exclusion gel restricting the parameters To test the validity of this result 3 other sets. albumin volume of distribution 3 This excluded vol of experimental data were fitted using these identical val. ume is larger in skin and tendon then in skeletal muscle ues of mecf and fclear muscle and only adjusting the. Page 10 of 29,page number not for citation purposes.
BMC Clinical Pharmacology 2003 3 http www biomedcentral com 1472 6904 3 3. Comparison,or 3semi log,of antecubital, right PBPK model predictions line and experimental data squares for EDTA 58 plotted using linear. Comparison of antecubital PBPK model predictions line and experimental data squares for EDTA 58 plotted using linear. left or semi log right, renal clearance The result of this procedure are shown in antibiotics listed in Table 3 amoxicillin piperacillin. figure 6 for the experimental data of Orlando et al 38 cefatrizine ceforanide flucloxacillin and dicloxacillin. second row Ladegaard Pedersen et al 39 third row The influence of the protein albumin binding on the. and Prescott et al 40 bottom row The agreement pharmacokinetics of these solutes is characterized by the. between the PBPK model and the experimental data is default PKQuest values for KAi in the different organs. quite good except for the long time data of Prescott et al Table 6 see Appendix II and III and the experimental. 40 This discrepancy is expected since the inulin clear values for the fraction bound in plasma fp Table 1 The. ance in the experiments of Prescott et al was non linear effect of including a capillary permeability limitation was. decreasing by about 50 at low concentrations long investigated for these solutes because as discussed above. times It is not clear why the data in the other three exper see eq 6 one would predict that solutes with a high. iments in fig 6 do not show this marked non linearity amount of protein binding should be capillary permeabil. ity limited All the other parameters were identical to. Figures 7 8 9 10 11 12 compare the PBPK model predic those used in figs 2 3 4 5 The addition of a capillary per. tions with experimental data for the six lactam meability limitation provides a significant improvement. Page 11 of 29,page number not for citation purposes. BMC Clinical Pharmacology 2003 3 http www biomedcentral com 1472 6904 3 3. Comparison,for 4experimental,of PBPK linear,data of left. or semi log,predictions,and bottom,experimental,row data for morphine 6 glucuro.
Comparison of PBPK linear left or semi log right plots of model predictions and experimental data for morphine 6 glucuro. nide for experimental data of Lotsch et al 59 top row and Penson et al 42 bottom row. Page 12 of 29,page number not for citation purposes. BMC Clinical Pharmacology 2003 3 http www biomedcentral com 1472 6904 3 3. Comparison,for 5experimental,of PBPK linear,data of left. or semi log, right plots of model predictions and experimental data for morphine 3 glucuro. Comparison of PBPK linear left or semi log right plots of model predictions and experimental data for morphine 3 glucuro. nide for experimental data of Penson et al 60, in the fit between the PBPK model and the experimental This new PBPK parameter set Table 6 also provided. data for the two antibiotics with the highest degree of good fits not shown to the other solutes that have been. binding dicloxacillin 97 bound fig 12 and flucloxa previously investigated with PKQuest propranolol 7. cillin 93 bound fig 11 For ceforanide fig 10 D2O and ethanol 6 anesthetic gases and toluene 5. which is 82 bound there is a slight improvement in the The slightly modified Maple worksheets describing these. fit with the addition of a small permeability limitation solutes are available on the PKQuest web site http. The value of the PS product for these three permeability www pkquest com. limited solutes is 11 3 ml min 100 g fclear 0 25 for. dicloxacillin 7 0 ml min 100 g fclear 0 344 for flu Discussion. cloxacillin and 5 ml min 100 g fclear 0 52 for cefora Volume of distribution of selected extracellular solutes in. nide For the other antibiotics amoxicillin piperacillin humans. and cefatrizine with protein binding of 62 or less the Table 1 summarizes the experimental measurements in. addition of a capillary permeability limitation does not humans of the steady state volume of distribution Vss for. significantly improve the fit For these flow limited antibi mannitol EDTA amoxicillin morphine 3 glucuronide. otics amoxicillin piperacillin cefatrizine there is only 1 morphine 6 glucuronide and inulin In order to be. adjustable parameter the renal clearance For the capil included in this table solutes had to meet the following. lary permeability limited solutes ceforanide flucloxacil criteria 1 extracellular distribution 2 low level of. lin dicloxacillin there are two adjustable parameters the plasma protein binding 3 no evidence of any unusual. renal clearance and fclear muscle tissue binding or accumulation 4 major excretory path. way is renal 5 linear pharmacokinetics and 6 published. Page 13 of 29,page number not for citation purposes.
BMC Clinical Pharmacology 2003 3 http www biomedcentral com 1472 6904 3 3. Comparison, 6 of PBPK linear left or semi log right plots of model predictions and experimental data for inulin. Comparison of PBPK linear left or semi log right plots of model predictions and experimental data for inulin The parame. ters rclr mecf and fclear muscle were adjusted to give the optimal fit to the data of Odeh et al 37 top row These values. of mecf and fclear muscle were then used to fit the experimental data of Orlando et al 38 second row Ladegaard Peder. sen et al 39 third row and Prescott et al 40 bottom row varying only the renal clearance to obtain the best fit. Page 14 of 29,page number not for citation purposes. BMC Clinical Pharmacology 2003 3 http www biomedcentral com 1472 6904 3 3. Figure 7 of,Comparison,experimental data,of Sjovall. linear left,predictions,experimental data for amoxicilllin for. Comparison of PBPK linear left or semi log right plots of model predictions and experimental data for amoxicilllin for. experimental data of Sjovall et al 61 top row and Arancibia et al 62 bottom row The flow limited PBPK model is used. no capillary permeability limitation,Page 15 of 29.

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Mouth and Teeth - KidsHealth

Mouth and Teeth KidsHealth

your teeth healthy, like fresh fruits and vegetables, and foods that can hurt your teeth, like sugary drinks and candy. Look through supermarket advertisements and magazines, and cut out pictures of foods. Sort your pictures into two groups: foods that help your teeth and foods that can hurt your teeth. Glue your pictures on the "Healthy Tooth ...

Mini-Diagnostic - Edition 2.4 - Final - Ivy Global

Mini Diagnostic Edition 2 4 Final Ivy Global

YOUR NAME (PRINT): LAST FIRST MI Ivy Global | SAT Mini-Diagnostic 3 SAT This exam is a short diagnostic to help you assess your general strengths and ...

Research Product 98-36 - DTIC

Research Product 98 36 DTIC

assist in evaluation of ways to implement this training. The Battle Captain training materials have application beyond Infantry. 14. SUBJECT TERMS Battle Captain, Battle Staff Training, TTP, Computer-based Training 15. NUMBER OF PAGES 87 16. PRICE CODE 17. SECURITY CLASSIFICATION OF REPORT Unclassified NSN 7540-01-280-5500 18. CLASSIFICATION OF ...

World War One Aircraft Models -

World War One Aircraft Models igavh2 xara hosting

1 World War One Aircraft Models I have always held a fascination with early military aircraft. Before I retired I served for 27 years in the Royal Air Force, then a further 20 years as a Military Aerospace Technical Author. Although, as most modelers, I got involved in the world of construction kits at an early age, I stopped for most



Diameter tudung buah jamur tiram putih diamati sejak tubuh buah pada baglog sudah siap untuk dipanen. Dari tabel tersebut dapat dilihat diameter tudung buah pada baglog dengan perlakuan B3 (50% Daun pisang kering + 50% Sabut kelapa) memberikan pengaruh untuk diameter tudung buah yang paling panjang. Panjang tudung buah tersebut termasuk dalam


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A Smoothed Particle Hydrodynamics: Basics and Applications

A Smoothed Particle Hydrodynamics Basics and Applications

Smoothed Particle Hydrodynamics was originally developed as a probabilistic meshfree particle method for simulating astrophysical problems [Lucy, 1977], [Gingold & Monaghan, 1977]. It was later modified as a deterministic meshfree particle method and applied to continuum solid and fluid mechanics [Monaghan, 1994], [Monaghan, 1992].


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The Merriam-Webster Dictionary defines Socialism as a way of organizing a society in which major industries are owned and controlled by the government rather than by individual people and companies . 9 Historically, this type of thinking would be taboo to the culture, but it is now being accepted. It is seen as a way to achieve equality. It is ...

The Great Depression Lesson 1 - Measuring the

The Great Depression Lesson 1 Measuring the

n A copy of The Great Depression: ... (Answers in the deflation circle of Visual 1.3 ... Measuring the Great Depression. depression Lesson 1 | Measuring the Great ...