ARTICLES
Physiolog ical Modeling of Disposition of Potential Tumor-Imaging Radiopharmaceuticals in Tumor-Bearing Mice DAVIDW. A. BOURNE'^, JEFFJ. JACOBS*, ALMAHAWALUDDIN*§, D. J . MADDALENA~, J. G. WILSON~, AND R. E. B O Y D ~ Received October 4, 1990, from the 'College of Pharma
Universi of Oklahoma, Health Sciences Center, 1770 N. Stonewall, Oklahoma City, Oklahoma, 731 17-1223, the *Deparfment of Pharmacy, giversity oIb,eensland, St. Lucia, 4067, Queensland, Australia, and the 'Isotope Accepted for Division, Australian Nuclear Science and Technology Organization, Private Mail Bag No. 7, Menai, 2234 NSW, Australia. publication June 30,1991. 5Present address: S. Laut U.K.M. Sabah, 88996 Kota Kinabalu, Sabah, Malaysia.
Abstract 0 Radiopharmaceuticals have great potential in the early
detection of human tumors. Three potential 98mTc-labeledplatinum compounds based on cisplatin have been synthesized and tested in tumored mice. This report presents the analysis of the disposition data obtained after a single intravenous injection with an empirical, physiologically based pharmacokinetic model. The radioactivity of each radiopharmaceutical after administration was measured in blood, urine, and 15 tissues, including tumor. Parameters included in the model were tissue volumes (experimentallydetermined), tissue blood flows (determined from literature values), tissue:blood extraction ratios (determined by nonlinear least-squares regression with MULTI-FORTE), and clearance terms (also determined by nonlinear least-squares regression). Data were weighted by the reciprocal of the square of the observed values. Good fits to the experimental data were obtained. As expected, the compound producing the best tumor:blood proflle (3) also had the highest tumor extraction ratio (6.2 versus 2.0 and 1.3 for 1 and 2. respectively).Total body clearance values for the radioactivtty associand ated with the three compounds 1-3 were calculated to be 0.09,0.04, 0.016 mumin, respectively. Analysis of data with such an empirical, physiologically based model may assist future development of suitable tumor-imaging agents.
The early detection and classification of human tumors is a major goal in the fight to overcome cancer. The special attraction of radiopharmaceutical techniques is the ability to detect and locate tumors by external imaging after administration of trace amounts of drug and radioactivity. The objective is to produce a radiopharmaceutical that will carry a gamma-emitting isotope to the tumor mass in preference to other tissues. Thus, a clear image of the tumor mass may be detected. Currently, gallium-67 citrate is used extensively for tumor detection. However, it has some disadvantages, including inability to detect tumors Radioactivity ("10dose per g) versus time in tumor tissue. Key: (0) 1, observed; (-) 1, calculated; (U) 2, observed; (. * . 2, calculated; (0)3, observed; (- - -) 3, calculated; ( 0 ) control, observed; (- - - -) control, calculated. a )
These results support previous claims12 that 3 has great promise as a tumor-imaging agent. The control, sodium [99mTclpertechnetate,produced a tumor:blood ratio of 1and a tumor:muscle ratio of 10 during the 1-4-h postdose period. Tumor:plasma and tumor:muscle ratios previously reported for lg5"Pt-1abeled cisplatin ranged from 2 to 6 and from 6 to 10, respectively,5 over a 4-24-h post dose period. The earlier results of Wolf and Manaka4 with cisplatin suggest more modest results of 1.2 and 3.1 for the tumor:blood and tumor: muscle ratios, respectively, a t 24 h, when calculated on the basis of percent dose per weight of tissue. Radioactivity values for 2 in liver and spleen were high and remained high throughout the study period. Some of the radioactivity may have been lost from the platinum moiety and retained by these tissues, or particulate material containing radioactivity may have been injected with the compound and subsequently retained by the liver and spleen. Double-labeled cisplatin has been studied in mice and rats to determine the lability of the Ptligand bond. In mice, there appears to be good correspondence between the two isotopes 410 I Journal of Pharmaceutical Sciences Vol. 81, No. 5,May 1992
U
cecum,and rectum could not be explained without separating the radioactivity into t i m e and contents components. The parameter values determined experimentally and those obtained from the literature are presented in Tables I and 11. The best fit values for other parameters of the model are shown in Tables I11 and IV. Figure 4 shows the final model used in data analysis. Drug distribution to muscle, skin, bone, heart, bladder, gall bladder, kidney, tumor, and carcass was based on simple mass balance equations, with the b1ood:tissue extraction ratio describing the equilibrium between blood and tissue. Blood flow to the spleen, stomach, gut, cecum, rectum, and liver reflected portal circulation. Progressively later peaks in measured radioactivity prompted the separation of gut, cecum, and rectum measurements into tissue and contents components. This addition to the model decreased the WSS and resulted in a lower Akaike information criterion value.21 Renal and nonrenal clearances of radioactivity were defined as exiting from the venous component of the model. Because of the number of parameters involved, the data were analyzed five times for each compound, with the run producing the lowest WSS considered the best. The final parameter values are shown in Table IV. The lines drawn in Figures 1-3 indicate the success of the data analysis. The data are generally well described by the model-predicted lines. With well-characterized radiopharmaceuticals, it has been possible to use external imaging of selected regions of intact rats23 and patients.6 Especially when applied to patient data, this technique makes it possible to obtain significant information about the biodistribution of these compounds by using a reduced pharmacokinetic model with subsystems. One limitation of this technique, similar to that of the present study, is that the various chemical forms, bound and free, are not separately measurable. Also, only limited regions of the body can be "sampled". This limitation may require calculation of some "compartments" by difference, with an associated increase in the measurement error and, thus, higher parameter variability. For this technique to be useful in humans, considerable quality control and toxicity information is required. Tissue distribution studies of new radiopharmaceuticals in a number of control and tumor-bearing animals still
Table ICFlow Ratea of Compounds In Tlssues
Vein and artery' Lung' Liver' Spleenb Kidney' MuscleC SkinC Bone' Heart' Bladderd Stomachb Gutb
Cecumb Rectumb Tumore Gall bladderd Carcass'
~
Tissue
Weight (9) of Tissue
1
2
3
Control
272 272 109 8.9 79 29 14 10 17 0.11 11 46 13 13 6.3 0.064 7.6
230 230 94 4.8 68 26 12 8.9 15 0.094 10 42
207 207 84 5.1 60 23 11 7.9 13 0.080 8.3 35 9.1 12 3.7 0.038 5.0
282 282 112 7.8 81 31 14 11 17 0.18 11 46 16 13 8.9 0.059 6.9
11 11
1.9 0.045 4.7
'From ref 1 1 ; scaled by weight. Apportioned among spleen, stomach, gut, cecum, and rectum by weight with total from ref 11. =Apportioned among muscle, skin, and carcass by weight with total from ref 1 1 . Calculated by using the same flow rate per gram as muscle. Calculated by using 1 1.6mUh/g (from ref 12).'Calculated as described in the text. Table Ill-Extraction Ratlor Detwmlned by Nonllnear Regre8alon Analyslr
Tissue Liver Spleen Kidney Muscle Skin Bone Lung Heart Bladder Stomach Gut
Table &Experimentally Determlned Welghts of Tissues of Tumor-Bearlng Ylce'
Flow Rate (mL/h) of:
Tissue
Cecum Rectum Tumor Gall bladder Carcass
Extraction Ratio of: 1
2
3
Control
1.2 0.25 3.0 0.20 0.47 0.32 0.57 0.23 0.57 6.4 1.2 0.48 0.92 2.0 0.97 0.50
3.8 1.3 2.1 0.12 0.20 0.27 0.55 0.24 0.31 3.0 0.95 1.29' 0.45 1.3 1.8 0.51
0.86 0.37 0.98 0.18 0.39 0.33 0.74 0.32 0.71 12.8 2.2 1.1 0.77 6.2 1.5 0.56
0.62 0.20 0.34 0.13 0.44 0.070 0.33 0.20 0.83 14.4 12.7' 0.075' 4.0' 1 .l 1 .o
0.49
1
2
3
Control
22.3 0.482 0.965 1.09 0.190 0.337 8.51 3.97 2.38 0.166 0.106 0.0323 0.230 0.990 0.276 0.268 0.540 0.0188 1.722
19.1 0.414 0.828 0.981 0.1 1 1 0.289 7.55 3.5 2.10 0.143 0.0902 0.0240 0.231 0.962 0.257 0.251 0.167 0.0129 1.21
17.1 0.370 0.739 0.951 0.127 0.239 6.51 3.00 1 .81 0.137 0.0871 0.0198 0.206 0.874 0.226 0.292 0.320 0.0107 1.13
22.9 0.496 0.991 1.10 0.160 0.408 8.96 4.06 2.48 0.162 0.119 0.0522 0.227 0.930 0.324 0.267 0.765 0.0171 0.880
afford a rapid and precise method of studying whole-body disposition. With physiological modeling of these data, it is possible to determine key disposition parameters, such as the in vivo tissue extraction ratio. In the present study, radioactivity measured was not separated into the various chemical (bound and free)forms that the compoundscould potentially produce in vivo.SJSJ6 However, the end result of this endeavor is to produce a radiopharmaceutical entity capable of visualizing tumors in vivo. It is the radioactivity that is detected; thus, modeling the disposition of radioactivity seemed to be appropriate, at least for these initial studies. With more time and resources, it may be possible to chemically identify most of the species involved, and if these compounds are clinically usell, this work should be completed.
Average of 3-5 mice per time point, with 7-9 time points determined. b T i ~ ~and u e contents. CCalculatedas total body weight minus the total weight of all other tissues measured.
It is possible to model mathematically the disposition of radioactivity in blood and various tissues oftumor-bearing mice
Total body weight Venous blood Arterial blood Liver Spleen Kidney Muscle Skin Bone Lung Heart Bladder Stomach Gutb
Cecumb Rectumb Tumor Gall bladder Carcass' a
'Values poorly estimated by nonlinear regression.
Conclusions
Journal of Pharmaceutical Sciences 1 411 Vol. 81, No. 5, May 1992
Table IV-Clearance and Other Parameters Detennlned by Nonllnear Regrerslon
Parameter
Value of Parameter for: 1
2
3
Control
0.37 0.61 0.31 0.24 0.038 0.016 5.1 1 0.23
0.34 0.25' 0.44 0.34 0.033 0.044 2.2 0.18
0.26 0.87 0.80 0.34 0.0051 0.027 0.62 0.32
0.10b 0.20b 0.177' 1 0.0' 0.0' 0.007' 1.14 0.07
'
Fraction of sample consisting of tissue and contents that is tissue. First-order rate constant (h-l) for transfer from gut contents to cecum contents. dFirst-order rate constant (h-I) for transfer from cecum contents to rectum contents. First-order rate constant (h-') for transfer from rectum contents. 'Clearance value (mUh) for drug excreted into urine. Clearance value (mLh) for drug excreted by nonrenal pathways. a
'Values poorly estimated by nonlinear regression.
after administration of potential tumor-imaging agents. Imperfect as the present analysis is, it quantitates concisely the relative distribution of the radioactivity within the tumorbearing animal and may suggest future directions in the development of other tumor-imaging radiopharmaceuticals. This study also indicates that data of tissue radioactivity values versus time can be analyzed simultaneously with current microcomputer software and/or hardware combinations.
References and Notes Lentle, B. C. In Current Applications in Radwpharmacology; Billinghurst, M. W., Ed.; Pergamon: Sydney, 1986;pp 48-61. Wolf, W.; Manaka, R. C.; In alls, R. B. In New Develo ments in Radwphurmaceuticals and t b e l l e d Compounds;IAE[ Vienna: 1973;pp 205-220. Smith, P. H. S.; Taylor, D. M. J . N w l . Med. 1974,15,349-351. Wolf, W.; Manaka, R. C. J . Clin. Hemutol. 1977,7, 79-95.
412 1 Journal of Pharmaceutical Sciences Vol. 81, No. 5, May 1992
5. Farris, F.F.; King, F. G.; Dedrick, R. L.; Litterst, C. L. J . Pharmmokinet. Bwpharm. 1985,13,13-39. 6. Shani, J.; Bertram, J.; Russell, C.; Dahalan, R.; Chen, D. C. P.; Parti, R.; Ahmadi, J.; Kempf, R. A.; Kawada, T. K.; MugGa, F. M.; Wolf, W. Cancer Res. 1989,49,1877-1881. 7. Baer, J.; Harrison, R.; McAuliffe, C. A.; Zaki, A.; Sharma, H. L.; Smith, A. G. Znt. J . Appl. Radiat. Zsotop. 1985,36,181. 8. Robins, A. B.; Leach, M. 0. Cancer Treat. Reports 1983, 67, 245-261. 9. Haber, M. T.; Cooper, A. J. L.; Rosenspire, K. C.; Ginos, J. Z.; Rottenberg, D. A. J . Labelled Compd. Radwphnrm. 1985, 22, 609-516. 10. Awaluddin, A. B., Ph.D. Thesis; University of Queensland, St. Lucia, Queensland, Australia, 1986. 11. Awaluddin, A. B.; Jacobs, J. J.; Bourne, D. W. A.; Maddalena, D. J.; Wilson, J. G.; Boyd, R. E. A pl. Radiut. Zsotop., Znt. J . Radiut. Appl. Znstr. Part A 1987,3Lf671-674. 12. Awaluddin, A. B: Jacobs, J. J.; Bourne, D. W. A.; Maddalena, D. J.; Wilson, J. it.; Boyd, R. E. Proc. Vth Znt. Sympos. Radwharmacology, Buenos Aires, Ar entina, Oct. 1986;Progress in $adiophurmmology, 1987,pp 1-%l, 1987 13. Maddalena, D. J. Publication E572.Australian Atomic Energy Commission, Lucas Heights, NSW Australia, 1983. 14. Bischoff, K.B. Bull. Math. Bwl.1986,48,309-322. 15. Farris, F. F.; Dedrick, R. L.; King, F. G. Toxicol. Lett. 1988,43, 117-137. 16. King, F. G.; Dedrick, R. L.; Farris, F. F. J . Phnrmacokinet. Bwpharm. 1986,14,131-155. 17. Dedrick, R.L.; Forrester, D. D.; Cannon, J. N.; El Dareer, S. M.; Mellett, L. B. Biochem. Phurmacol. 1973,22,2405-2417. 18. Mantyla, M.J. Cancer Res. 1979,39,2304-2306. 19. Gear, C. W. Communications of the ACM 1969,14,176-179. 20. Bourne, D. W. A. Computer Meth. Programs Biomed. 1986,23, 277-281. 21. Akaike, H. ZEEE Tmns. Automat. Control 1973,19,716-723. 22. Vermorken, J. B.; van der Vijgh, W. J. F.; Pinedo, H. M. Res. Commun. Chem.Path. Pharmacol. 1980.28.319-328. 23. Brechner, R . R.; DAr enio, D. Z.; Dahalan, R.; Wolf, W. J . Pharm. Scz. 1986,75, %73-877.
Acknowledgments Supported in part by Australian Institute of Nuclear Science and Engineerin grant 85/86.Almah Awaluddin waa eu ported during this study p6y a scholarship from the Malaysian jublic Services Department.
Physiolog ical Modeling of Disposition of Potential Tumor-Imaging Radiopharmaceuticals in Tumor-Bearing Mice DAVIDW. A. BOURNE'^, JEFFJ. JACOBS*, ALMAHAWALUDDIN*§, D. J . MADDALENA~, J. G. WILSON~, AND R. E. B O Y D ~ Received October 4, 1990, from the 'College of Pharma
Universi of Oklahoma, Health Sciences Center, 1770 N. Stonewall, Oklahoma City, Oklahoma, 731 17-1223, the *Deparfment of Pharmacy, giversity oIb,eensland, St. Lucia, 4067, Queensland, Australia, and the 'Isotope Accepted for Division, Australian Nuclear Science and Technology Organization, Private Mail Bag No. 7, Menai, 2234 NSW, Australia. publication June 30,1991. 5Present address: S. Laut U.K.M. Sabah, 88996 Kota Kinabalu, Sabah, Malaysia.
Abstract 0 Radiopharmaceuticals have great potential in the early
detection of human tumors. Three potential 98mTc-labeledplatinum compounds based on cisplatin have been synthesized and tested in tumored mice. This report presents the analysis of the disposition data obtained after a single intravenous injection with an empirical, physiologically based pharmacokinetic model. The radioactivity of each radiopharmaceutical after administration was measured in blood, urine, and 15 tissues, including tumor. Parameters included in the model were tissue volumes (experimentallydetermined), tissue blood flows (determined from literature values), tissue:blood extraction ratios (determined by nonlinear least-squares regression with MULTI-FORTE), and clearance terms (also determined by nonlinear least-squares regression). Data were weighted by the reciprocal of the square of the observed values. Good fits to the experimental data were obtained. As expected, the compound producing the best tumor:blood proflle (3) also had the highest tumor extraction ratio (6.2 versus 2.0 and 1.3 for 1 and 2. respectively).Total body clearance values for the radioactivtty associand ated with the three compounds 1-3 were calculated to be 0.09,0.04, 0.016 mumin, respectively. Analysis of data with such an empirical, physiologically based model may assist future development of suitable tumor-imaging agents.
The early detection and classification of human tumors is a major goal in the fight to overcome cancer. The special attraction of radiopharmaceutical techniques is the ability to detect and locate tumors by external imaging after administration of trace amounts of drug and radioactivity. The objective is to produce a radiopharmaceutical that will carry a gamma-emitting isotope to the tumor mass in preference to other tissues. Thus, a clear image of the tumor mass may be detected. Currently, gallium-67 citrate is used extensively for tumor detection. However, it has some disadvantages, including inability to detect tumors Radioactivity ("10dose per g) versus time in tumor tissue. Key: (0) 1, observed; (-) 1, calculated; (U) 2, observed; (. * . 2, calculated; (0)3, observed; (- - -) 3, calculated; ( 0 ) control, observed; (- - - -) control, calculated. a )
These results support previous claims12 that 3 has great promise as a tumor-imaging agent. The control, sodium [99mTclpertechnetate,produced a tumor:blood ratio of 1and a tumor:muscle ratio of 10 during the 1-4-h postdose period. Tumor:plasma and tumor:muscle ratios previously reported for lg5"Pt-1abeled cisplatin ranged from 2 to 6 and from 6 to 10, respectively,5 over a 4-24-h post dose period. The earlier results of Wolf and Manaka4 with cisplatin suggest more modest results of 1.2 and 3.1 for the tumor:blood and tumor: muscle ratios, respectively, a t 24 h, when calculated on the basis of percent dose per weight of tissue. Radioactivity values for 2 in liver and spleen were high and remained high throughout the study period. Some of the radioactivity may have been lost from the platinum moiety and retained by these tissues, or particulate material containing radioactivity may have been injected with the compound and subsequently retained by the liver and spleen. Double-labeled cisplatin has been studied in mice and rats to determine the lability of the Ptligand bond. In mice, there appears to be good correspondence between the two isotopes 410 I Journal of Pharmaceutical Sciences Vol. 81, No. 5,May 1992
U
cecum,and rectum could not be explained without separating the radioactivity into t i m e and contents components. The parameter values determined experimentally and those obtained from the literature are presented in Tables I and 11. The best fit values for other parameters of the model are shown in Tables I11 and IV. Figure 4 shows the final model used in data analysis. Drug distribution to muscle, skin, bone, heart, bladder, gall bladder, kidney, tumor, and carcass was based on simple mass balance equations, with the b1ood:tissue extraction ratio describing the equilibrium between blood and tissue. Blood flow to the spleen, stomach, gut, cecum, rectum, and liver reflected portal circulation. Progressively later peaks in measured radioactivity prompted the separation of gut, cecum, and rectum measurements into tissue and contents components. This addition to the model decreased the WSS and resulted in a lower Akaike information criterion value.21 Renal and nonrenal clearances of radioactivity were defined as exiting from the venous component of the model. Because of the number of parameters involved, the data were analyzed five times for each compound, with the run producing the lowest WSS considered the best. The final parameter values are shown in Table IV. The lines drawn in Figures 1-3 indicate the success of the data analysis. The data are generally well described by the model-predicted lines. With well-characterized radiopharmaceuticals, it has been possible to use external imaging of selected regions of intact rats23 and patients.6 Especially when applied to patient data, this technique makes it possible to obtain significant information about the biodistribution of these compounds by using a reduced pharmacokinetic model with subsystems. One limitation of this technique, similar to that of the present study, is that the various chemical forms, bound and free, are not separately measurable. Also, only limited regions of the body can be "sampled". This limitation may require calculation of some "compartments" by difference, with an associated increase in the measurement error and, thus, higher parameter variability. For this technique to be useful in humans, considerable quality control and toxicity information is required. Tissue distribution studies of new radiopharmaceuticals in a number of control and tumor-bearing animals still
Table ICFlow Ratea of Compounds In Tlssues
Vein and artery' Lung' Liver' Spleenb Kidney' MuscleC SkinC Bone' Heart' Bladderd Stomachb Gutb
Cecumb Rectumb Tumore Gall bladderd Carcass'
~
Tissue
Weight (9) of Tissue
1
2
3
Control
272 272 109 8.9 79 29 14 10 17 0.11 11 46 13 13 6.3 0.064 7.6
230 230 94 4.8 68 26 12 8.9 15 0.094 10 42
207 207 84 5.1 60 23 11 7.9 13 0.080 8.3 35 9.1 12 3.7 0.038 5.0
282 282 112 7.8 81 31 14 11 17 0.18 11 46 16 13 8.9 0.059 6.9
11 11
1.9 0.045 4.7
'From ref 1 1 ; scaled by weight. Apportioned among spleen, stomach, gut, cecum, and rectum by weight with total from ref 11. =Apportioned among muscle, skin, and carcass by weight with total from ref 1 1 . Calculated by using the same flow rate per gram as muscle. Calculated by using 1 1.6mUh/g (from ref 12).'Calculated as described in the text. Table Ill-Extraction Ratlor Detwmlned by Nonllnear Regre8alon Analyslr
Tissue Liver Spleen Kidney Muscle Skin Bone Lung Heart Bladder Stomach Gut
Table &Experimentally Determlned Welghts of Tissues of Tumor-Bearlng Ylce'
Flow Rate (mL/h) of:
Tissue
Cecum Rectum Tumor Gall bladder Carcass
Extraction Ratio of: 1
2
3
Control
1.2 0.25 3.0 0.20 0.47 0.32 0.57 0.23 0.57 6.4 1.2 0.48 0.92 2.0 0.97 0.50
3.8 1.3 2.1 0.12 0.20 0.27 0.55 0.24 0.31 3.0 0.95 1.29' 0.45 1.3 1.8 0.51
0.86 0.37 0.98 0.18 0.39 0.33 0.74 0.32 0.71 12.8 2.2 1.1 0.77 6.2 1.5 0.56
0.62 0.20 0.34 0.13 0.44 0.070 0.33 0.20 0.83 14.4 12.7' 0.075' 4.0' 1 .l 1 .o
0.49
1
2
3
Control
22.3 0.482 0.965 1.09 0.190 0.337 8.51 3.97 2.38 0.166 0.106 0.0323 0.230 0.990 0.276 0.268 0.540 0.0188 1.722
19.1 0.414 0.828 0.981 0.1 1 1 0.289 7.55 3.5 2.10 0.143 0.0902 0.0240 0.231 0.962 0.257 0.251 0.167 0.0129 1.21
17.1 0.370 0.739 0.951 0.127 0.239 6.51 3.00 1 .81 0.137 0.0871 0.0198 0.206 0.874 0.226 0.292 0.320 0.0107 1.13
22.9 0.496 0.991 1.10 0.160 0.408 8.96 4.06 2.48 0.162 0.119 0.0522 0.227 0.930 0.324 0.267 0.765 0.0171 0.880
afford a rapid and precise method of studying whole-body disposition. With physiological modeling of these data, it is possible to determine key disposition parameters, such as the in vivo tissue extraction ratio. In the present study, radioactivity measured was not separated into the various chemical (bound and free)forms that the compoundscould potentially produce in vivo.SJSJ6 However, the end result of this endeavor is to produce a radiopharmaceutical entity capable of visualizing tumors in vivo. It is the radioactivity that is detected; thus, modeling the disposition of radioactivity seemed to be appropriate, at least for these initial studies. With more time and resources, it may be possible to chemically identify most of the species involved, and if these compounds are clinically usell, this work should be completed.
Average of 3-5 mice per time point, with 7-9 time points determined. b T i ~ ~and u e contents. CCalculatedas total body weight minus the total weight of all other tissues measured.
It is possible to model mathematically the disposition of radioactivity in blood and various tissues oftumor-bearing mice
Total body weight Venous blood Arterial blood Liver Spleen Kidney Muscle Skin Bone Lung Heart Bladder Stomach Gutb
Cecumb Rectumb Tumor Gall bladder Carcass' a
'Values poorly estimated by nonlinear regression.
Conclusions
Journal of Pharmaceutical Sciences 1 411 Vol. 81, No. 5, May 1992
Table IV-Clearance and Other Parameters Detennlned by Nonllnear Regrerslon
Parameter
Value of Parameter for: 1
2
3
Control
0.37 0.61 0.31 0.24 0.038 0.016 5.1 1 0.23
0.34 0.25' 0.44 0.34 0.033 0.044 2.2 0.18
0.26 0.87 0.80 0.34 0.0051 0.027 0.62 0.32
0.10b 0.20b 0.177' 1 0.0' 0.0' 0.007' 1.14 0.07
'
Fraction of sample consisting of tissue and contents that is tissue. First-order rate constant (h-l) for transfer from gut contents to cecum contents. dFirst-order rate constant (h-I) for transfer from cecum contents to rectum contents. First-order rate constant (h-') for transfer from rectum contents. 'Clearance value (mUh) for drug excreted into urine. Clearance value (mLh) for drug excreted by nonrenal pathways. a
'Values poorly estimated by nonlinear regression.
after administration of potential tumor-imaging agents. Imperfect as the present analysis is, it quantitates concisely the relative distribution of the radioactivity within the tumorbearing animal and may suggest future directions in the development of other tumor-imaging radiopharmaceuticals. This study also indicates that data of tissue radioactivity values versus time can be analyzed simultaneously with current microcomputer software and/or hardware combinations.
References and Notes Lentle, B. C. In Current Applications in Radwpharmacology; Billinghurst, M. W., Ed.; Pergamon: Sydney, 1986;pp 48-61. Wolf, W.; Manaka, R. C.; In alls, R. B. In New Develo ments in Radwphurmaceuticals and t b e l l e d Compounds;IAE[ Vienna: 1973;pp 205-220. Smith, P. H. S.; Taylor, D. M. J . N w l . Med. 1974,15,349-351. Wolf, W.; Manaka, R. C. J . Clin. Hemutol. 1977,7, 79-95.
412 1 Journal of Pharmaceutical Sciences Vol. 81, No. 5, May 1992
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Acknowledgments Supported in part by Australian Institute of Nuclear Science and Engineerin grant 85/86.Almah Awaluddin waa eu ported during this study p6y a scholarship from the Malaysian jublic Services Department.
