Eur J Clin Pharmacol (1995) 48:489-494 © Springer-Verlag 1995 PHARMACOKINETICS AND DISPOSITION O. J. Degrossi • M. Ortiz • E. B. Degrossi H. Garcia del Rio • J. C. Barreira • D. Messina E. Kerzberg • E. J. A. Roldfin • E. Montuori • A. P6rez Lloret Serum kinetics, bioavailability and bone scanning of "mTc-labelled sodium olpadronate in patients with different rates of bone turnover Received: 30 June 1994/Accepted in revised form: 29 March 1995 Abstract The activity of olpadronate labelled with technetium-99m(99mTc) was monitored in plasma and urine samples after single oral (925 MBq 99mTc/10 mg, coadministered with 50 mg cold drug) and intravenous (925 MBq 99mTc/5 mg) administrations to two groups of patients with different rates of bone turnover. The first group comprised high bone turnover (HBTO) patients suffering from Paget's bone disease; the sec- ond group comprised patients with normal to low bone turnover (NBTO) having the diagnosis of rheumatoid arthritis and secondary osteoporosis. Kinetic variables were correlated with anthropomorphometric variables, biological markers of bone metabolism and plasma proteins. Data were also obtained after repeatedly dos- ing the HBTO patients. Additionally, Paget's bone and healthy bone (PB/HB) uptake before and after low- dose oral treatment were assessed by means of scintig- raphy. Results showed that most of the kinetic variables did not differ between the two groups of patients, except for a greater V~ and smaller blood area under the curve AUC in the patients with HBTO. After a repeated-dose administration period, the blood AUC activity and Whole Body Retention (WBR) of the HBTO patients tended to be similar to those of the NBTO patients. In both groups, after oral dosing, the Cma~ was 20 times lower than the C0.5 after i.v. injection, and the oral O. J. Degrossi - M. Ortiz ' E. B. Degrossi - H. Garcia del Rio Nuclear Medicine Center, German Hospital, Buenos Aires, Argentina J. C. Barreira - D. Messina Department of Rheumatology, C. Argerich Hospital, Buenos Aires, Argentina E. Kerzberg Department of Rheumatology, JM Ramos Mejia Hospital, Buenos Aires, Argentina E. J. A. Roldan ([]) • E. Montuori - A. Pdrez Lloret Department of Clinical Pharmacology, Gador SA, Darwin 429, 1414, Buenos Aires, Argentina bioavailability ranged from 3% to 4%. Finally, the plasma t,/2B ranged from 9 to 14 h. Correlation coefficients were obtained from multiple regression analysis; kinetic variables showed very low correlations with anthropomorphometric measurements. In con- trast the Vs~ and WBR were significantly correlated with serum alkaline phosphatase levels and the Vs~ also with urine hydroxyproline levels. Plasma protein con- centration was also correlated with excretion parame- ters such as CLp and plasma t,/:13 after an oral dose. Scintigraphic studies in the HBTO group allowed bone selectivity to be seen through skeletal drug uptake. The 15 Pagetic lesions analysed in the HBTO group showed a decrease in PB/HB ratio from 3.8 in the basal study to 2.7 after olpadronate administration for 30 days at the rate of 50 rag/day. In conclusion, the kinetic profile of 99mTc-labelled olpadronate, mainly AUC and WBR, showed a dependence upon bone metabolism and seemed unrelated to body size variables. HBTO patients showed a lower blood AUC but a higher Vs~. Both vari- ables may have been reflecting the fact that the drug binds selectively with calcified tissues and, in turn,with the target compartment. Scintigraphy confirmed the labelled-compound bone selectivity as a desirable fea- ture for a bone-scanning agent. Key words Paget's bone disease, Osteoporosis, Olpa- dronate; bisphosphonates Nitrogen-containing bisphosphonates (NCBs) seem to have a double-action mechanism depending on the dosage. At high dose rates, they are potent inhibitors of bone resorption, and at lower dose rates, they act as modulators of the bone-remodelling processes, increasing skeletal mass [1-4]. The latter mechanism seems to be advantageous when bisphosphonates are employed in long-term treatments because it has no adverse consequences upon bone metabolism [4,5]. The dose-related mechanism may depend on saturation of
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`490 O SODIUM # ~.OH OLPADRONATE HO--p / h- -/ITCH= .t'CH3 U~(.; \ fN \ CH2 ~ CH~ H0 Jo//P\o.Na 0 O {pIjOH / !jCH2 ,, / CH~ 0 "ll';I:: ............ 0 //\n. H o "' / CH2 ~ ~ .CH3 HOoCh 0 OLPADRONATE Fig. 1 A perspective view of anhydrous salt of sodium olpadronate and the technetium atom coordinated to two molecules of the protonated form of olpadronate different bone compartments. Bisphosphonate toler- ance and acceptance thereof is related to extraskeletal kinetic properties. Generally speaking, these are com- pounds showing low bioavailability, high osteotropism, long half-life in the skeleton and short half-life in plasma, they are not metabolized and most of them simply disappear by glomerular filtration [6,7]. The kinetic characteristics, namely disappearance, osteotro- pism and rapid excretion rate, account likewise for the low degree of exposure of extraskeletal tissues to bis- phosphonates and, consequently, for the absence of sys- temic toxic effects. Bisphosphonate salt low bioavailability and solubility are related to digestive system irritation, which is evidenced by symptoms ranging from simple dyspepsia to vomiting or gastri- tis. Thus, kinetic properties are of interest from different points of view. Olpadronate (WHO, proposed INN List 71, previously named dimethyl APD) is a new NCB (Fig. 1), which differs from disodium pamidronate, the standard NCB, in that it is 50 times more soluble in water at pH 7.0, 5 times more potent as an inhibitor of bone resorption [3] and may cause less disturbances in the multicellular bone unit functioning (osteoclast- osteoblast interactions), a characteristic associated with bone biomechanical yielding [8]. The toxicologi- cal tests show a similar profile to that of disodium pamidronate [9] but tolerance data in humans are still very scarce, though necessary, to describe the kinetic plasma profile and bone uptake of this new NCB. Because adequate methods for the direct assessment of olpadronate in biological fluids are still under devel- opment, this first study was intended as an indirect approach to describe the kinetics of olpadronate in humans. The activity observed in plasma and urine after oral and intravenous administration on an HBTO group and another NBTO group of patients is reported here. Kinetic variables were correlated with anthropo- morphometric measurements, bone metabolism tracers and the plasma proteins. Data were also obtained after repeatedly dosing the HBTO patients. As a secondary aim, healthy bone and Paget's bone captation before and after low-dose treatment was assessed in the HBTO group, by means of scintigraphy, in order to describe 99mTc-labelled olpadronate use as a bone-scanning agent within the same protocol. Material and methods Subjects Since NCBs are potent inhibitors of bone resorption, tending to accumulate on the skeleton, and the research protocol required the use of repeated doses, an agreement was reached with the Research and Ethics Committees of the Buenos Aires German, Argerich and Ramos Mejia Hospitals to the effect that only patients suffering from bone metabolism disturbances, for whom the use of the said compounds could be beneficial, were admitted and experimentation with healthy volunteers was avoided. The final protocol was approved by the Ministry of Health and Social Welfare. Two different groups of patients were selected. The first one included elderly male HBTO subjects in whom Paget's disease of bone had been diagnosed, according to clinical, biochemical and radiological criteria. The second group included adult NBTO women, with osteoporosis secondary to rheumatoid arthritis and previous corti- coid exposure. Diagnosis was based on the radiological finding of at least one non-traumatically flattened vertebra and current serum alkaline phosphatase and urinary hydroxyproline levels under the upper normal value (Table I). As there were no healthy volunteers in this group, the term "normal" relates only to the current level of biological markers of bone metabolism and does not necessar- ily exclude qualitative abnormalities provoked by the disease itself or previous treatments. Calcaemia, the plasma electrophoretic proteinogram and creatininaemia were also assessed in all patients and mid-molecule Parathyroid Hormone (PTH) fragments in the HBTO group. The main anthropomorphometric characteristics were assessed, and laboratory tests were performed during the month prior to the active trial phase_ Table 1 Main characteristics of selected patients in the normal to low bone turnover (NBTO) group and high bone turnover (HBTO) group. Means (SE). Urinary HOP upper normal value= 77 mg/24 h; serum alkaline phosphatase upper normal value=130 UI.1-1 Group NBTO HBTO HBTO/NBTO (n) (6) (5) (%) Urinary hydroxyproline HOP (mg/24 h) Serum alkaline phosphatase (UI-1-1) Age (years) Body weight (kg) Relative body weight (% ideal) Body surface area (m 2) Sex (F/M) 54.0 (4.3) 89.0 (14.8) + 65.0 119.2 (7.2) 287.8 (130.2) + 140.0 35.3 (2.2) 67.6 (2.7) + 91.0 64.4 (6.7) 75.1 (4.6) + 16.6 + 8.8 (3.9) + 11.6 (5.2) + 31.8 1.64 (0.8) 1.83 (0.1) + I1.6 6/0 0/5
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`Once the patients had been selected, their written consent was obtained for their stay in the German Hospital, under the auspices of the Nuclear Medicine Center, and for the performance and monitoring of the kinetic tests. During their hospital stay, the patients were maintained under similar dietary conditions and the active trial phase was begun under fasting conditions. Tracer, drug administration and protocol Each patient was dosed intravenously with 99mTc-1abelled olpadronate (925 Mbq 99mTc/5 mg olpadronate). Labelling of the radiopharmaceutical compound was done by means of a method based on the electrolytic generation of Sn 2+ (Centellokit, Gador SA, Buenos Aires) [10, 11]. Radiopharmaceutical controls performed by the chromatographic method [11] allowed the lots containing more than 1% free technetium or colloids to be discarded. In addition, scintigraphy provided evidence for the lack of a liver image (caused by colloids) or of thyroid or gastric mucosa concentrations (caused by the presence of free technetium). After intravenous injection, blood samples were obtained at intervals of 0.5, 1, 2, 4, 6, 8, 12 and 24h after the injection. Radioactivity was assessed in plasma aliquots by means of a "well counter" type scintillation detector with a spectrometer. Seven days after the first trial, patients were confined again in order to repeat the trial this time upon the administration of an oral dose of 925 MBq 99'~Tc/10 mg of olpadronate solution associated with 50 mg (one enteric-coated tablet) cold drug. HBTO patients underwent a 30-day treatment on a 50-rag/day oral dose, at the end of which the kinetic test was repeated for the third time, after a new intravenous administration of 925 MBq-99mTc/5 mg olpadronate. Mathematical model for statistical calculation Blood assessments were obtained as percentage per litre in relation to the total dosage of the labelled compound. In urine, radioactiv- ity was expressed as apercentage of the dose. On the basis of these relations, quantities are presented as mass units (mg. ml 1) per mil- ligram administered dose. Time units are expressed in hours and decimal fractions. To perform the kinetic variable calculation, a computer program for an IBM PC was used. The area under the curve (AUC) was taken between the first (extrapolated at 0 h) and the last blood concentration measurements. Truncated areas were calculated according to the trapezoidal method. Plasma disappear- ance mean rate was calculated using linear regression. A new redis- tribution phase up to 1-5 h and a 13-disappearance phase from the 6th h after administration were specifically measured. Blood clear- ance was calculated according to the following formula: CL = dose/total AUC. A volume of distribution, as estimated in the stationary state of blood concentrations (V~), and a volume of distribution up to a theoretical zero concentration (f/z), were assessed. Bioavailability (f) was determined by means of the for- mulaf = (Ae p.o./Ae i.v.) x (D i.v./D p.o.) x 100, where Ae is the amount of activity excreted through the urine during 24 h and D is the total administered dose. Scintigrams In all the kinetic tests performed intravenously, bone scintigrams were taken at 3-, 4- and 6- h intervals, using a gamma camera and an MDS A2/A3 computer system, analog and digital images being obtained. Due to the characteristic kinetics of olpadronate, the best images were recorded from 4 to 6 h after administration. In all HBTO patients, scintigraphic images were obtained in the basal study performed intravenously and again after the 30-day oral treatment. In order to determine the evolution of bone lesions, two methods were employed. The first was based on the determination, 491 against digital images, of regions of interest (ROIs) over the lesions, normal bone and soft tissue background with the same number of pixels [10], and calculation of the ratio of lesions to normal bone. The second method was used on analog images, following the method described by Patel et al [12], as employed by Ryan et al [13]. Scans were scored using a semiquantitatlve scale: 0 = no appar- ent lesions; 1 =just detectable increased activity; 2=easily detectable increased activity without loss of definition of adjacent bone; 3 = easily detectable increased activity but with loss of definition of adjacent bone and 4 = easily detectable activity from lesion with none visualized from adjacent normal bone. The stud- ies were assessed under blinded conditions, withno knowledge of whether they were pre or post-treatment. For each patient a mean score was obtained by adding the individual lesion score and divid- ing by the number of lesions. Data analysis The curves shown in the figures appear as mean values (SEM) unless (SD) is indicated. Students t-test was used for similar samples while comparing the data obtained through one or the other routes of administration and the t-test was used for independent data while comparing the HBTO and NBTO groups. Bone scan scores were compared using the dependency test. Kinetic variables were corre- lated with biochemical and anthropomorphometric variables by the multiple linear regression test. Body surface area was calculated by means of a nomogram. The ideal weight was assessed according to the method of the Society of Actuaries (Diem K, 1965). A TAD- POLE III program, in its IBM PC version, was used, with a two- tail, P < 0.05 value being deemed as significant. Results No serious or unexpected events were recorded during the study. In addition to the biochemical data shown in Table I, the following values were obtained for the patients: mid-molecule PTH fragment 70.6 (11.9) pg-lml, calcaemia 9.4 (0.2)rag% and creatininaemia 0.95 (0.07 mg. dl- 1). Kinetics and bioavailability Table 2 shows the kinetic variables calculated after oral and intravenous administration in the HBTO or NBTO patient groups (see complete curves in Fig. 2). After oral dosing, the Cm~x values were 20 times lower than the Cos values after intravenous injection. Average bioavailability of the oral solution was 3.4 (1.9)% in the HBTO group, 3.6(1.2)% in the NBTO group and 3.6 (0.4)% in the HBTO group after repeated oral doses. The Vss in orally treated NBTO patients was 2.8 times lower than in HBTO patients and 3.6 times lower than in the same group when treated intravenously. Fig. 3 shows the AUC in each of the patients studied. AUCs were smaller in the HBTO group after oral and intravenous administrations. No other meaningful differences between the two groups were detected. According to urinary activity, whole body retention was estimated at 34.6% after the first intravenous dose in HBTO and decreased to 28.9% after 30 days oral treatment, these figures being comparable to the 28.7 %
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`492 Table 2 Mean kinetic variables from blood samples of normal to low bone turnover (NBTO) patients or high bone turnover (HBTO) patients treated either with single intravenous or oral 99mTc-labelled olpadronate. Last cohmm shows HBTO patients treated repeatedly with oral cold olpadronate and then assessed after intravenous 99mTc-labelled olpadronate Group After single doses After repeated oral doses NBTO p.o. NBTO i.v. HBTO p.o. HBTO i.v. HBTO i,v. n 6 6 5 5 4 Mean Cm,x 2.85 2.08 -- (ng-ml-1) Mean tm~(h) 2.79 - 2.05 - - Mean C 24 h 0.67 2.07 0.53 1.67 1.90 (rig- ml- i) AUC 0-24 h 32.63 186.15 27.78 145.23 158.28 (ng-h-ml -~) AUC /max p.o. 7.34 c 86.16 a'° 1.97 39.19 ~ -- V~(1) 13.90 50.44 38.29 67.08 64.64 Vz(1) - 62.76 87.01 84.93 CLp(ml' rain 1) 15.34 85.13 36.21 104.65 91.03 tv=13 (h) b 13.8 d 9.55 12.01 9.86 10.80 MRT (h) 11.16 d 10.43 14.31 11.19 11.98 aAt 0.5 h bFrom 6 to 24 h c/,/---- 4 dn= 5 noted in the NBTO group. The t,/~13 values ranged from 9 to 14 h, and mean retention time values between 10 and 14 h. A significant (P < 0.05) correlation was found between serum alkaline phosphatase and V,,(r = 0.68) and WBR (r = 0.81); V,, also correlated with urinary hydroxyproline (r = 0.74) after oral administration; CLp correlated with albumin (r = 0.82) and t,/213 with the/~- protein fraction (r = 0.96) after oral adminis- tration. Very low correlations were found between kinetic variables and anthropomorphometric measure- ments (r between 0.56 and -0.40). There was a high positive correlation between circulating PTH levels and C24(r = 0.80), AUC (r = 0.82) and Cm,x(r = 0.81) and a negative correlation between these levels and CLp (r = -0.83); however, since they were analysed for only five individuals, they were not statistically significant. Post-intravenous kinetic variables were not correlated with post-oral variables and showed a different Activity (by mg of labelled drug) 1.2 1 ........................................................................................... 0.8 0.6 0.4 S 0.2 ORAL ° ~ , __ 5 10 15 20 25 Time (h) Low BTO o High BTO Fig. 2 Plasma activity of 99'~Tc-labelled olpadronate in patients with normal to low or high bone turnover (BTO) after oral and intravenous single administrations behaviour pattern, which perhaps depended on the concentration. Scintigrams Scintigraphic studies carried out on HBTO patients (Fig. 4) allowed selectivity to be seen through skeletal uptake and the rapid alterations in the pathological 13"1 g ¢- (5 rj 300 28O 260 240 220 2O0 180 160 140 120 100 8O 6O 40 20 0 HBTO LB'TO ,, -.<----" ....... /j i "" ,J~,, ORAL IV IV AFTER SINGLE SINGLE REPEATED DOSE DOSE DOSES 99m Fig. 3 AUC of Tc-labelled olpadronate plasma levels in patients with high (HBTO) or normal to low (NBTO) bone turnover after oral and intravenous doses
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`Fig. 4 A,B Effects of oral sodium olpadronate daily administration (50 mg per day, 30 days) in a patient with Paget's disease. Scan images performed with 99mTc-labelled olpadronate (A) before and (B) after treatment areas in three out of the four patients on whom post-treatment control could be performed. The 15 Pagetic lesions analysed before and after treatment, according to Roi's method, showed a decrease in PB/HB ratio from 3.8 (1.5) in the basal study to 2.7 (1.4) after olpadronate administration for 30 days at the rate of 50 mg per day (P < 0.05). The second method used for studying the evolution of the affected bone areas (semiquantitative) indicated similar varia- tions. Table 3 shows the values obtained as average number of lesions per patient. The mean scores decreased from 2.40 to 1.60 (P < 0.05). Discussion The first issue to arise from these studies is related to the use of the tracer element associated with the bis- phosphonate. Some authors find differences in the kinetic data when comparing, for instance, 14C-labelled Table 3 Means (SD) of semiquantitative bone scan scores on HBTO patients (Paget's disease) lesions, pre and post 30 days 50 mg oral olpadronate treatment Patient Number of lesions Bone scan score Pre-treatment Post-treatment 1 3 3.0 2.7 ~ 2 5 2.6 1.4 b 3 1 2.0 4 3 2.3 1.3 b 5 3 1.7 1.0 b Total 15 Mean - 2.40 (0.54) 1.60 (0.75) ~Pain unchanged b Improvement 493 pamidronate with 99mTc-labelled pamidronate [14]. These differences seem to arise when the preparations have not been duly checked and there is consequently a greater colloid captation by the liver [15]. For this reason, chromatographic controls were carried out for the assessment of free technetium and labelled colloid particles, and the preparations which did not meet the selected specifications were rejected. The efficacy of this behaviour was subsequently corroborated by the absence of images in the liver and in those tissues (thyroid, gastric mucosa) which concentrate pertech- netate (free Tc). These precautions being taken, there is a surprising similarity between the 99mTc-labelled pamidronate [10] curves and those obtained by high- performance liquid chromatography (HPLC) [16] in spite of the different methodologies involved. Care must also be taken when interpreting the absorption curves since the Tc-labelled compound is a dimer (Fig. 1); in the case of olpadronate, however, the dimerization does not seem to affect its bioavailability. Olpadronate, like the other bisphosphonates, shows little absorption. The oral solution bioavailability is variable, its mean rate being 3--4%. Bioavailability has been estimated to be 1-4% for etidronate tablets [17]; 0.3% for pamidronate tablets [16]; 2-3 % for tiludronate capsules I18] and 2 % for clodronate capsules [19]. Although these calcula- tions have been obtained by different methods, they all show considerable individual variability. Generally, the plasma kinetics of bisphosphonates has little to do with their bone activity. It may mostly depend on how much bisphosphonate is available in an active bone section such as the bone apposition surface compartment [20]. The fact that the Vs~ is smaller and AUC is bigger in the NBTO group patients demonstrates the above-men- tioned dependence. The current impossibility of esti- mating the kinetics of the assumed active bone compartment from the plasma activity levels causes posology schedules to be based on the dose-response curves obtained from bone metabolism tracers rather than on the peripheral kinetic variables [3]. As pamidronate was previously studied under an analo- gous protocol [10], some considerations can be made. Both compounds behave in a similar way to the plasma absorption and distribution curve profile and the bone uptake rate. Similarities have also been described in animal species when both compounds are dosed intra- venously (Mondelo N. et al., unpublished communi- cation). Olpadronate demonstrates, in HBTO or NBTO patients, a mean t,/213 of 9-14 h and a higher WBR% than previously described in the pamidronate report [10], thereby leading us to assume that there may be the possibility of skeletal and extraskeletal accumua- tion upon repeated doses, which is not the case with pamidronate. A known fact is that bisphosphonate skeletal accumulation depends on dosage and on the BTO rate [20, 21]. In this trial, performed on HBTO and NBTO patients, there seem to be no major differences in many variables of the plasma olpadronate curves upon administration of single intravenous or
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`494 oral doses. The higher V~ and lower AUC found in the HBTO group could be attributed to higher bone turnover, perhaps reflecting a sizable active compart- ment as discussed above, but groups differ also regard- ing sex and age. Nevertheless, both kinetic variables in the HBTO group tend to approximate the NBTO val- ues after a course of treatment that decreased olpadronate uptake in bone lesions. Moreover, the lack of correlation with anthropomorphometric variables (sex related), and no clear differences between groups, strongly support the idea that bone metabolism is more influential than sex and age. This fact should be confirmed with a different study protocol. The influence of bone metabolism on olpadronate kinetics becomes more evident from the correlation between basal alka- line phosphatase levels and the Vss or the WBR%. We have not been able to prove, with this group of patients, that the same correlation occurs with serum PTH lev- els, due to the fact that it was measured in only five patients, but coefficients were found to be high. Plasma proteins also appear to bear some influence. A 30.2% plasma binding has been described for pamidronate [22], probably to globulin fractions and transferrin. The correlation between t,/213 and 13-fraction of plasma pro- teins seems to indicate that something similar happens with olpadronate. In the repeated-dose phase implemented, in spite of the small number of patients, we observed that the 50-mg/day olpadronate dose aroused, by the 30-day, stage, a positive response in the activity rates in three out of four patients. Scintigraphy demonstrated the skeletal selectivity of the compound and may also be suggested to be an indicator of the evolution of Paget's disease during bone treatment. Acknowledgements The authors wish to thank N61ida Mondelo for providing unpublished data on 99mTc-labelled NCBs in rabbits and rats. The study was supported in part by a grant from Gador SA (1991-1993), Buenos Aires. The study was partially presented at the Xlth International Conference on Calcium Regulating Hormones (ICCRH), Florence, April 1992 and the XIIth Congress of the Latin American Association of Biology and Nuclear Medicine Societies (ALASBIMN), Madrid, 1992. Olpadronate has been named in previous works as mildronate or dimethyl-APD. References I. Boonekamp PM, L6wik CWGM, van der Wee-Pals LJA, van Wijk-van Lennep MLL, Bijvoet OLM (1987) Enhancement of the inhibitory action of APS on the transformation of osteo- clast precursors into resorbing cells after dimethylation of the amino group. Bone Miner 2:29-42 2. L6wik CWGM, van der Pluijm G, van der Wee-Pals LJA, Bloys-van Treslongs de Groot H, Bijvoet OLM (1988) Migration and phenotypic transformation of osteoclast pre- cursors into mature osteoclasts: The effects of a bisphospho- nate. J Bone Miner Res 3:185-192 3. Schweitzer DH, Zwinderman AH, Vermeij P, Bijvoet OLM, Papapoulos SE (1993) Improved treatment of Paget's disease with dimethylaminohydroxypropylidene bisphosphonate. J Bone Miner Res 8:175-182 4. Bijvoet OLM (1989) Pamidronate (APD) in cancer therapy: the pharmacological background. In : Rubens R (ed) The man- agement of bone metastases and hypercalcaemia by osteoclast inhibition. Hogrefe and Huber, New York, pp 13-18 5. Valkema R, Papapoulos V, Pauwels EKJ, Bijvoet OLM, Papapoulos SE (1987) No evidence of cumulative effect of low dose APD on bone remodelling during four year continuous treatment in osteoporosis. J Bone Miner Res 4 [Suppl]: $370 6. Wingen F, Schmfihl D (1987) Pharmacokinetics of the osteotropic diphosphonate 3-amino-l-hydroxypropane-l,1- diphosphonic acid in mammals. Arzneimittelforschung/Drug Res 37:1037-1042 7. M6nkk6nen J, Koponen HM, Ylitalo P (1989) Comparison of the distribution of three bisphosphonate in mice. Pharmacol Toxicol 65 : 294-298 8. Ferretti JL, Mondelo N, Vazquez S, Bogado CE, Zanchetta JR (1991) Mineral density and structural properties of male and female rat femora as affected by dimethyl pamidronate. J Bone Miner Res 6 [Suppl 1]:S128 9. Mondelo N, Rold/m EJA, Bur G, Rubinstein C, Coco R, Montuori E (1992) Extraskeletal toxicity of aminobisphospho- hates compounds administered by oral and parenteral routes. Bone Miner 17 [Suppl 1]:S181 10. Degrossi OJ, Oliveri P, Garcia del Rio H, Labriola R, Artagaveytia D, Degrossi EB (1985) Technetium-99mAPD com- pared with technetium-99m MDP as a bone scanning agent. J Nucl Med 26:1135-1139 11. Degrossi O J, Oliveri P, Labriola R, Degrossi EB, Campanelli H, Garcia del Rio H, Altschuler N, Artagaveytia D (1986) Clinical trial of several compounds labelled with 99~'Tc utilizing an elcctrolytical method. In: Cox PH, Touyfi E (eds) New per- spectives in nuclear medicine. (Monographs in nuclear medicine, vol 2), Gordon and Brech S.C. Publishers, New York, pp 181-206 12. Patel U, Gallaher S J, Boyle IT, McKillop JH (1990) Serial bone scans in Paget's disease: development of new lesions, nature variation in lesion intensity and nature changes seen after treat- ment. Nucl Med Commun 1:747-760 13. Ryan PG, Gibson T, Fogelman I (1992) Bone scintigraphy fol- lowing intravenous pamidronate for Paget's disease of bone. J Nucl Med 33:1589 1593 14. Daley Yates PT, Bennet R (1989) A comparison of the phar- macokinetics of ~4C-labelled APD and 99Tc-labelled APD in the mouse. Calcif Tissue Int 45:198 15. Fogelman I, Lazarus C (1989) Comparison of the pharmaco- kinetics of ~4C-labelled APD and 99mTc-labelled APD in the mouse. Calcif Tissue Int 45:198-199 16. Daley Yates PT, DodweI1 D J, Pongchaidecha M, Coleman RE, Howel A (1991) The clearance and bioavailability of pamidronate in patients with breast cancer and bone metas- tases. Calcif Tissue Int 49:433-435 17. Fogelman I, Smith L, Mazess R, Wilson MA, Bevan JA (1986) Absorption of oral diphosphonate in normal subjects. Clin Endocrinol 24:57-62 18. Reginster JYL (1992) Oral tiludronate: pharmacological prop- erties and potential usefulness in Paget's disease of bone and osteoporosis. Bone 13:351-354 19. Yakatan GJ, Poynor WJ, Talbert RL, Floyd BF, Slught CL, Ampulski RS, Benedict JJ (1982) Clodronate kinetics and bioavailability. Clin Pharmacol Ther 31 : 402-410 20. Fogelman I, Bessent RG, Cohen HN, Hart DM Lindsay R (1980) Skeletal uptake of diphosphonate. Method for predic- tion of postmenopausal osteoporosis. Lancet II : 667-670 21. Leyvraz S, Hess V, Flesch G, Bauer J, Hauffe S, Ford JM, Burckhardt P (1992) Pharmacokinetics of pamidronate in patients with bone metastases. J Nat Cancer Inst 84:788-792 22. Daley Yates PT, Cal JC, Cockshott A, Pongchaidecha M, Gilchrist K (1992) Plasma protein binding of APD: role of cal- cium and transferrin. Chem Biol Interact 81:79-89
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