MR imaging properties and pharmacokinetics of MnDPDP in healthy volunteers

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1 Ata Radiologia ISSN: (Print) (Online) Journal homepage: MR imaging properties and pharmaokinetis of MnDPDP in healthy volunteers Chen Wang, P. B. Gordon, S. O. Hustvedt, D. Grant, A. Tufte Sterud, I. Martinsen, H. Ahlström & A. Hemmingsson To ite this artile: Chen Wang, P. B. Gordon, S. O. Hustvedt, D. Grant, A. Tufte Sterud, I. Martinsen, H. Ahlström & A. Hemmingsson (1997) MR imaging properties and pharmaokinetis of MnDPDP in healthy volunteers, Ata Radiologia, 38:5, To link to this artile: Published online: 4 Jan 21. Submit your artile to this journal Artile views: 42 View related artiles Citing artiles: 13 View iting artiles Full Terms & Conditions of aess and use an be found at Download by: [ ] Date: 13 January 218, At: 1:46

2 Ata Radiologia 38 (1 997) Printed in Denmark. All rights reserved Copyright Atu Rudiologiu 1997 ACTA RADIOLOGICA ISSN MR IMAGING PROPERTIES AND PHARMACOKINETICS OF MnDPDP IN HEALTHY VOLUNTEERS C. WANG~, P. B. GORDON~, S.. HUSTVEDT, D. GRANT, A. TUFTE STERUD~, I. MARTIN SEN^, H. AHLSTROM~ and A. HEMMINGSSON Department of Diagnosti Radiology, University Hospital, Uppsala, Sweden; and Researh & Development, Nyomed Imaging AS, Oslo, Norway. Abstrat Purpose: Thirteen male volunteers were studied to evaluate the MR imaging properties and pharmaokinetis of 1 mm mangafodipir trisodium infusion (MnDPDP, Teslasan). Material and Methods: Doses of 5 and 1 ymolkg b.w. were administered by bolus injetion ( 4 min) to 5 subjets, and by infusion (2 min) to 8 subjets, with a 3week washout between doses. Infusion subjets underwent MR imaging. Results: At 1 h after infusion, the plasma onentration of Mn was redued to 15% of the maximum value. Fifteen to 2% of Mn was reovered in the urine, and 56% was reovered in the faees. The rapid initial plasma learane of Mn is onsistent with both rapid tissue uptake and rapid renal elimination. Inreases in signal intensity were apparent on T1weighted images of the liver, panreas, spleen, renal ortex and the renal medulla, but not in regions of the brain proteted by an intat bloodbrain barrier. Inreases were seen in the horoid plexus and pituitary. Contrastrelated adverse events, only flushing of moderate intensity, ourred in bolus injetion subjets. Conlusion: At 5 and 1 pmolkg, mangafodipir produes relatively longlasting enhanement of several abdominal organs, inluding the liver, panreas and kidney. Key words: Contrast medium, manganese; MnDPDP, MR. Correspondene: Chen Wang, Department of Diagnosti Radiology, University Hospital, S Uppsala, Sweden. FAX hen.wang@radiol.uu.se Aepted for publiation 11 November Mangafodipir trisodium (MnDPDP; manganese (11) N,N dipyridoxylethylenediaminen,n diaetate5, 5 bis(phosphate) sodium salt) infusion, hereafter referred to as mangafodipir, is a preparation of a manganese (Mn) helate that has been developed as a ontrast agent for MR imaging of the hepatobiliary system. Mangafodipir is designed to target normally funtioning tissues of hepatoellular origin. Following i.v. administration, the released Mn + is taken up by liver parenhyma and other ells (2, 22, 29, 39, 46). In rats and dogs, the majority of Mn is eliminated in faees ( 182), mainly via biliary exretion, and a smaller fration is rapidly exreted renally, oupled to a metabolite of dipyridoxyl diphosphate (DPDP), shortly after dosing, whereas the ligand is rapidly and virtually ompletely exreted in the urine (2,22). Mangafodipir is a paramagneti omplex and in aqueous solution its T1 relaxivity is similar to that of gadopentetate dimeglumine (GdDTPA), but in liver tissue 3 min after administration of mangafodipir, T1 relaxivity was 3fold higher than 3 min after administration of GdDTPA (1, 48). The in vivo MR properties of mangafodipir are most probably due to intraellular uptake of Mn (12,2,22,39, 46, 49). The paramagneti properties of Mn failitate more rapid TI relaxation, resulting in inreased MR signal intensity of target tissues on TI weighted images. Mangafodipir has been shown to be generally 665

3 C. WANG ET AL. safe in a omprehensive programme of safety testing in a variety of in vivo and in vitro studies (2, 5, 1, 18, 2426, 28, 5). In tumour models, it has been shown that hepatoellular arinomas may enhane either positively or negatively, ompared with normal liver, depending on the degree of differentiation (33, 37), and that mangafodipirenhaned rims around malignant primary and seondary tumours are assoiated with zones of malignant infiltration, parenhymal ompression and biledut proliferation (38). Reently, several reports have been published based on results from linial phase I (3) and I1 (1, 4, 21, 41, 42, 44, 5 1) trials in whih a onentration (5 mm) and formulation of mangafodipir slightly different from that used in the European phase I11 trials (1 mm) was investigated. The purpose of this study was to determine the pharmaokinetis, inluding the metaboli profile, of 1 mm mangafodipir at 2 doses, 5 and 1 ymovkg b.w., given as an infusion (as in the European phase I11 programme), and as a bolus injetion. An additional main objetive was to ompare the MR effets of infusing the 2 doses on seleted anatomial regions, to investigate the diagnosti utility of the agent. Material and Methods Trial design The trial was performed as a singleblind, 2period trial in 13 healthy male volunteers, aged 2132 years (mean 25 years). The volunteers were divided into groups; 8 reeived the ontrast medium by slow infusion and 5 reeived it as a bolus injetion. All 13 subjets reeived 2 doses, 5 and 1 pmolkg b.w., with a washout period of at least 3 weeks between dose periods. The standard (5 ymolkg) dose was administered first, with the subjets blinded to the dose. Only the 8 volunteers given the ontrast medium as an infusion were examined by MR. The trial protool was approved by the Swedish Medial Produts Ageny and the Ethis Committee of Uppsala University Hospital. Contrast medium and dosing Mangafodipir (Nyomed), at a onentration of 1 ymovml, was supplied in 5 ml vials (48). Eight infusion subjets were given mangafodipir by a 2 min infusion into a dorsal foot vein while lying on the table of the MR equipment. Subjets in the bolus injetion group were given eah dose in an arm vein over a maximum of 1 min (over 3247 s for the standard dose, and 4763 s for the high dose). In all subjets, 1 ml saline was used to flush the annula immediately after dosing, and this was followed by infusion of 5 ml of saline over about 1 h to failitate adequate diuresis in the early postdosing period. MR imaging protool MR imaging was performed with a Philips ACSII 1.5T system, using a body oil for abdominal organs and a head oil for head and brain strutures. Table 1 details the sequene parameters for the 4 imaging sequenes: a) T 1 weighted turbofield gradienteho axial abdominal sequene (T1 A); b) T2 weighted turbo spineho (SE) axial abdominal sequene (T2A); ) TIweighted SE axial brain sequene (TlB); and d) T1weighted SE oronal brain sequene for the pituitary (TIP). MR examinations were made just before the start of infusion and repeated at intervals during the following 24 h; additional delayed sans (from approximately 48 h up to 96 h after the end of infusion) were made on some volunteers (Table 2). Table 1 MR imaging sequene parameters Type of sequene T1A T2A T1B TIP T1weighted gradienteho T2weighted spineho TIweighted spineho T1weighted spineho TR, ms TE, rns Flip angle, O Field of view Aquisitions, n Matrix Orientation Slie thikness, mm Gap, mm Slies, n or 179x256 transaxial x256 transaxial x256 transaxial x256 oronal

4 MR PROPERTIES AND PHARMACOKINETICS OF MnDPDP Table 2 Time points for the MR imaging sans and number of subjets sanned at eah time poinl Type of sequene Time point T1A SIH dose* Before infusion During infusion After infusion 3 min 2 min 8 min 15 min 2 min 8 min 15 min 2 min 45 min 9 min 4h 8h 12 h 24 h 48 h 56h 72 h 96 h * SM dose=standard (5 pmol/kg)/high (1 pmol/kg) dose I 1 I MR assessments For the assessment of hanges in signal intensity (SI), the regions of interest (ROIs) were defined as: liver, spleen, panreas, renal ortex, renal medulla, pituitary gland, horoid plexus, thalamus, pallidum and erebral deep white matter. For eah san, images that best showed the tissues or organs on the same level were seleted and displayed onseutively on the sreen. ROIs were drawn within the required tissues or organs and kept at the same loation for eah san series. The ROIs were made as large as possible without introduing partialvolume effets aused by adjaent strutures suh as hepati vessels when measuring liver parenhyma, or renal pelvis and renal medulla when measuring renal ortex. Efforts were made to keep the size of the ROIs as onstant as possible for images from the different sans, espeially when subjets had been moved and repositioned for the delayed sans. A referene tissue was hosen for eah type of sequene. A ROI was drawn and SI measured within the referene in the same setion and in the same way as for the target tissues or organs. In T1A and T2A images, the spinaleretor musle was used as the referene for the abdominal organs; in TlB images, orbital or periranial fat was used as the referene for brain strutures; in T1P images, the erebrospinal fluid (CSF) was used as the referene for the pituitary. The mean SI was measured within the ROIs and the SI value for eah of the required items was then T2A SM dose* 718 Not auuliable TlB SM dose* TIP SM dose* I related to that of the hosen referene, to normalize the variation of the mahine s internal environment in the evaluation of ontrast effiay. Mean per ent hanges per sequene, tissue and time point were plotted by using the formula: [(SI in ROItime divided by SI in referenetime minus SI in ROIbaseline divided by SI in refereneba,,,ine) xloo] divided by (SI in ROIbaseline divided by SI in referene,as,,ine). The peak enhanement was ompared within eah subjet per sequene and tissue by alulating the perentage inrease ompared to baseline in the various SI measurements. Although in some ases postinfusion sans were aquired at time points later than 24 h after infusion, only the values for the time points up to 24 h are presented. Sine only a few subjets were examined at eah time point beyond 24 h (Table 2) the results ould not be ompared with the mean values obtained up to 24 h. For the majority of the tissues or organs, an overall piture of the enhanement pattern was evident from the measurements obtained in the 24h followup period. Safety Overall safety of the 2 doses and 2 modes of administration was investigated by losely observing and regularly questioning the subjets for the ourrene of adverse events during the 24h inhouse period after dosing, by questioning them at the 4day followup visit, and by monitoring hanges in heart rate and 667

5 C. WANG ET AL systoli and diastoli blood pressures at intervals up to 3 min after dosing. Blood samples obtained at 1, 4, 12,24 and 96 h after dosing were analysed for: serum aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, yglutamyl transferase, reatinine, reatinine kinase, urea, bilirubin, albumin, total protein, alium, aamylase and lipase; plasma noradrenaline, adrenaline, dopamine and zin (Zn); and routine haematology. Urine samples obtained 48,1224 and 96 h after dosing were monitored for hanges in urinary gluose, protein, red and white blood ell ounts, albumin, Naetylgluosaminidase, alkaline phosphatase and alanine aminopeptidase. Pharmaokineti assessments Blood samples for the determination of plasma Mn and Zn onentrations were drawn at 48, 12 and 1 h before dosing and at different time points up to 24 h after dosing (2, 5, 15 and 2 rnin after the start of infusion, and 2,5, 1, 15,2, 3,45 rnin and 1, 1.52, 4, 8, 12 and 24 h after the end of infusiodinjetion). Urine was olleted over defined intervals from 24 h before until 24 h after dosing, while faeal samples were olleted from 48 h before until 96 h after dosing. All samples were analysed for Mn ontent as desribed by TOFT et al. (49). The following pharmaokineti parameters were estimated for eah subjet: total plasma learane (CL); apparent volume of distribution at steadystate (Vd,,); halflives of the different plasma phases (t1,j; area under the plasma onentrationtime urve alulated by the trapezoidal rule and extrapo lated to infinity (AUC,,); maximal observed plasma onentration (Cmax); fration (f,) exreted in urine and faees. Pharmaokineti analysis was performed as desribed by TOFT et al. (49). The terminology and alulations are aording to Row LAND & TUCKER (43) and GIBALDI & PERRIER (17). Results Signal intensity measurements TlA sequene Eah of the abdominal tissues or organs examined showed an inrease in SI after the start of infusion of mangafodipir trisodium. Liver: In the liver (Fig. l), the maximum SI enhanement was seen 15 rnin after the end of the standarddose (5 pmolkg b.w.) infusion, and 2 rnin after the end of the highdose (1 pmolkg b.w.) infusion. With both doses, SI was already near maximal at the end of the 2min infusion period. The enhanement was more pronouned in the highdose group and the peak SI value over the baseline was 33% greater than that ahieved in the standarddose group; peak inreases in the standard and highdose groups were 77 and 1 lo%, respetively. Near maximal enhanement was maintained for a further 2 to 4 h, indiating a postdosing imaging window of approximately 4 h. Subsequently, the SI delined, and at 24 h it was about 15% above the preinfusion value (baseline). Panreas: In the panreas (Fig. 2), the SI inreased quikly after the start of infusion. At 2 min after the end of infusion, the enhanement had almost reahed its maximum; peak inreases in the a = 12 a 2 1 E 2 8 u. 6 a 4 w 2 2 b p o Fig. 1. Liver: MR SI profiles over time (NB, nonlinear time sale) for infusion subjets Pre (n=8) during and after infusion rnin rnin rnin rnin min rnin min rnin h h h h h of 2 doses of mangafodipir; mean perentage hange from Imaging time baseline +SD, T1A sequene. 668

6 MR PROPERTIES AND PHARMACOKINETICS OF MnDPDP Fig. 2. Panreas: MR SI profiles over time (NB, nonlinear time sale) for infusion subjets (n=8) during and after infusion of 2 doses of mangafodipir; mean perentage hange from baseline +SD, T1A sequene. al = 12 Q) 2 1 E Q) 4 CD 2 2 M O Panreas I IN F U S I N II POSTINFUSION I I I I I I I I I I I I Fig. 3. Spleen: MR SI profiles over time (NB, nonlinear time sale) for infusion subjets (n=8) during and after infusion of 2 doses of mangafodipir; mean perentage hange from baseline +SD, T1A sequene. al. al 4 3 n E 2 2 n. 1 Q n 2 M Pre rnin rnin rnin rnin rnin rnin rnin rnin h h h h h Spleen T I Imaging time I INFUSION II POSTINFUSION I Pre rnin rnin rnin rnin rnin rnin rnin rnin h h h h h Imaging time standard and highdose groups were 57 and 84% above baseline, respetively. The SI level was sustained for approximately 4 h and delined thereafter. At 24 h postinfusion it was about 3% above the baseline value. Although the peak value in the highdose group was about 2% greater than that in the standarddose group, the pattern of enhanement was similar in both dose groups. Spleen: In the spleen (Fig. 3), the SI inreased faster than in the liver and panreas, and the maximum value was reahed 5 min before the end of infusion. The enhanement over baseline was low in both dose groups, and the peak levels of enhanement reahed in the high and standarddose groups were 28% and 18%, respetively. The SI in the spleen started to derease as soon as the infusion ended, and had returned to baseline within 12 h. Renal medulla: The hanges in SI in the renal medulla (Fig. 4) were similar to those of the spleen. Enhanement inreased rapidly to maximum levels about 87% above baseline in the highdose group, and 48% above baseline in the standarddose group. The SI values dereased gradually and had returned to baseline by 824 h postinfusion. 669

7 C. WANG ET AL. Renal ortex: In the renal ortex (Fig. S), the enhanement pattern was similar to that in the liver: maximum SI values were reorded 2 rnin after the end of infusion in both dose groups. Peak enhanements were 16% and 83% above baseline, in the high and standarddose groups, respetively. Eight hours after the end of infusion, the SI in both dose groups had returned to near baseline values. SI measurements T2 sequene Only 3 sans were aquired at different time points: preinfusion, 2 min postinfusion and 4 h postin fusion. SIs were measured in the same tissues/organs as for T1A desribed above. No linially signifiant ontrast enhanement was seen in any of the tissues/organs monitored, in either dose group (data not shown), indiating that T2weighted sans are equivalent before and after the administration of mangafodipir. SI measurements TlB sequene There was no SI inrease in the thalamus, pallidum or erebral deep white matter after infusion of either the standard or high dose of mangafodipir. Obvious a,,e 1 a, 2 8 E 2 6. ' 4. g) 2 m 6 bp Renal medulla T T INFUSION Ii POSTINFUSION Pre min min min min min min min rnin h h h h h imaging time Fig. 4. Renal medulla: MR SI profiles over time (NB, nonlinear time sale) for infusion subjets (n=8) during and after infusion of 2 doses of mangafodipir; mean perentage hange from baseline +SD, T1A sequene. a,.= 12 P) 2 1 E.I 8 a 6. P) 4 n 2 2 H O Renal ortex w INFUSION II POSTINFUSION I I I I I I I 1 I I I I I Pre rnin min rnin min min rnin rnin min h h h h h imaging time Fig. 5. Renal ortex: SI profiles over time (NB, nonlinear time sale) for infusion subjets (n=8) during and after infusion of 2 doses of mangafodipir; mean perentage hange from baseline fsd, T1A sequene. 67

8 MR PROPERTIES AND PHARMACOKINETICS OF MnDPDP Fig. 6. Choroid plexus: MR SI profiles over time (NB, nonlinear time sale) for infusion subjets (n4) after in Q) 7 Choroid plexus dipir; mean perentage 6o hange from baseline +SD, TIB sequene. E 5 I I I I I fusion of 2 doses of mangafo a) 2, E 2 1 #2 O.L 5 pmol Ioo 1 pmol b Pre 45 min 1.5 h 4 h 8 h 24 h enhanement was noted in the horoid plexus, and the maximum SI value was seen at 1.5 h after the end of infusion (Fig. 6). The enhanement delined slowly and lasted for at least 48 h (only data up to 24 h are shown as not all subjets were sanned at later time points). The pattern of uptake was similar in both dose groups and the extent of uptake was not dosedependent: the peak value in the highdose group was 1% below that in the standarddose group. SI measurements TIP sequene In the pituitary (Fig. 7), a speial pattern of enhanement was observed. After infusion of the standard dose of mangafodipir, the SI ontinued to inrease up to and beyond 24 h. However, the rate of inrease beyond 45 min after the end of infusion was low. In some subjets the inrease ontinued for up to 72 h (data not shown). Sine sans beyond 24 h were not aquired for most of the volunteers, the time of maximum enhanement and the SI reovery are not reorded. However, after the standard dose, the enhanement at 24 h postinfusion was 56% over baseline and just before infusion of the high dose 4 weeks later it was 23% over the same baseline (data not shown). These data indiate a prolonged, slow and inomplete reovery in the period between the 2 doses. Similar enhanement patterns were seen after the standard and high doses, but the extent of enhanement with the high dose appears to be lower than with the low dose. However, the urves an not be diretly ompared beause of the Imaging time differene in the baseline values due to inomplete washout between doses. Results of followup examinations, i.e., MR imaging of 7 subjets about one year later, and analysis of blood samples obtained during the study for possible mangafodipirrelated hanges in levels of thyroid stimulating hormone, free thyroxine and triiodothyronine, showed that the MnDPDP administrationrelated SI inrease seen within the pituitary normalizes over time and that neither dose of MnDPDP had an effet on pituitary funtion. Safety No serious adverse events ourred during the ourse of the trial. Six of the 8 infusion subjets given the standard dose experiened a total of 7 adverse events other than dosingassoiated disomfort (gastroenteritis; headahe; sinusitis; ough; sensitivity to noise; ommon old 2 ases). Two experiened 3 events (headahe; tiredness 2 ases) with the high dose. None of the events was lassified as related to the ontrast medium; all were either present before the start of infusion or lassified as related to the proedure. Four of the 5 bolus injetion subjets given the standard dose experiened a total of 7 adverse events (nasal ongestion; nausea 2 ases; headwarmth 4 ases), 4 of whih were lassified as related to the ontrast medium. The 5 subjets given the high dose experiened a total of 15 events (nasal ongestion; feeling of pressure/pulsation in the throat; feeling of pressure in the ears 3 ases; nausea 3 ases; dizziness 2 671

9 C. WANG ET AL. ases; headwarmth 5 ases), 5 of whih (1 per subjet) were ontrastrelated. The only type of ontrastrelated adverse event was headwarmth of moderate intensity, and in eah ase it was reorded as visible flushing. The other events were all mild in intensity and lassified as related to the proedure. All subjets reovered from these events without any sequelae or need for mediation. Dosingrelated disomfort, sensation of warmth or oldness, was experiened only by bolus injetion subjets (3 with the standard dose and 2 with the high dose), and in eah ase it was mild in intensity. Of the hanges noted in the vital signs monitored, none were of linial importane, and very few of the hanges in blood pressure or pulse rate reorded at individual time points in individual subjets exeeded predetermined limits onsidered to indiate potential linially important hanges (2 mm Hg for blood pressure and 15 bpm for heart rate). Furthermore, there were no hanges in either blood hemistry or urine hemistry variables that were lassified as linially important. In addition, there was no measurable ateholamine release in any subjet that ould be related to ontrast administration. To summarize, no trends were apparent from the patterns of hanges seen in linial hemistry variables that were related to either the dose or rate of drug administration. Plasma onentrations of Zn dereased in the first 8 h after both infusion and bolus injetion of mangafodipir, but normal plasma Zn levels were generally restored within 24 h (data not shown). The hanges in plasma Zn levels were not onsidered to have any linial importane. Q. 7 Q Q 6 n E 5 2 y 4. 3 Q 2 9) 2 1 N o I I I I I I Pituitary T Pre 45 rnin 1.5 h 4h 8h 24 h Imaging time Pharmaokinetis The mean plasma onentrations of Mn following i.v. infusion of mangafodipir, orreted for individual baseline values (48 h before dosing) are presented in Fig. 8. A detailed desription of the pharmaokineti parameters derived from the infusion and injetion data is presented elsewhere (49). In all ases the halflife of the initial plasma elimination phase was short (<2 min), while the mean terminal plasma halflife (mean of the 2nd and 3rd elimination phases in subjets with 2 and 3 phases, respetively) of Mn was 5.3 to 11.4 h. The apparent volume of distribution ranged from.51 to 1.53 Vkg, and following both bolus injetion and infusion was redued with inreasing dose. Similarly, total plasma learane, between.36 and.57 l/h. kg, was also redued with inreasing dose. As expeted, maximal plasma onentrations of Mn inreased linearly with dose and were muh higher after bolus injetion than infusion. As a onsequene of the rapid elimination of Mn from the plasma, due to tissue uptake and exretion, by 1 h postdosing the plasma onentrations were substantially redued: to 11.5% and 15.9% of the maximal values in the standard and highdose infusion groups, respetively; in the bolus injetion groups the orresponding figures were 3.5% and 6.1% (data not shown). Mean umulative frations of the administered dose of Mn exreted in the urine up to 24 h after dosing, and in faees during the 4day followup period, orreted for endogenous amounts, were from r Fig. 7. Pituitary: MR SI profiles over time (NB, nonlinear time sale) for infusion subjets (n=8) after infusion of 2 doses of mangafodipir; mean perentage hange from baseline fsd, T1P sequene. 672

10 MR PROPERTIES AND PHARMACOKINETICS OF MnDPDP Fig. 8. Plasma onentration of Mn over time (NB, nonlinear time sale) for infusion subjets (n=8) during and after infusion of 2 doses of mangafodipir; mean onentration in pmov1 fsd. I M lo 5 umol pmo'l L m Q) I Pre 2 8 rnin rnin 14 to 2% and 52 to 61%, respetively, and overall reovery ranged between 72 and 75% (49). The majority of the Mn exreted in urine was reovered in the samples obtained 1 h after dosing and this has been shown in other studies to be in the form of Mn pyridoxylethylenediamine (MnPLED) (9). The fration of Mn eliminated in urine and faees was unaffeted by the rate of administration, but there was a tendeny towards inreased renal reovery and orrespondingly dereased faeal reovery with inreasing dose. Disussion The most pronouned ontrast enhanement in the abdomen after the administration of mangafodipir was seen in the liver, followed by the renal ortex and the panreas. In all 3 tissues there was a short phase of rapid enhanement followed by a plateau of stable ontrast enhanement, whih lasted longest in the panreas and was shortest in the renal ortex. Enhanement of the renal ortex delined relatively rapidly, that in the liver more slowly, and that in the panreas still slower. Maximal enhanement was greatest after the high dose in all 3 tissues. From the end of infusion, the useful ontrastenhaned imaging windows for these tissues i.e., when ontrast was near maximal lasted for about 1 h for the renal ortex, 4 h for the liver and 6 h for the panreas. However, it should be noted that in patients with hepatoellular arinoma, imaging at 24 h after the infusion of a 5 pmolkg dose of mangafodipir has proved to be very effetive in evaluating liver malignany (32). Although maximal enhane INFllSlON II POSTINFLISION I rnin rnin rnin rnin rnin min h h h h h Imaging time ment was more pronouned after the 1 pmolkg dose, the 5 pmol/kg dose was suffiiently effiaious for general imaging purposes. The spleen and the renal medulla also displayed dosedependent enhanement, but the degree of enhanement was relatively low in the spleen, and the timeintensity profile was irregular for the renal medulla, espeially after the standard dose. No ontrast enhanement was observed in regions of the brain proteted by an intat bloodbrain barrier. There were, however, inreases in SI in the horoid plexus and the pituitary gland. As the horoid plexus and the main part of the pituitary imaged (the glandular part) lak an intat bloodbrain barrier, as do other irumventriular organs, some degree of enhanement was not unexpeted, but the enhanement lasted longer than in any abdominal tissues or organs and was not dosedependent. This pattern of enhanement was partiularly evident in the pituitary, and ontrast was retained in the pituitary for a onsiderable length of time (Fig. 7). The mean baseline value before the seond dose was 23% higher than that before the first dosing, whih indiates that the mangafodipirrelated SI inrease in the measured area did not normalize during the 4 day followup and 3week washout period, although it was substantially below the value (i.e., 56%) reahed 24 h after infusing the standard dose. The prolonged enhanement in the horoid plexus lasting for several days was not unexpeted. The horoid plexus is overed by an epithelial ependyma whih is speialized not only for seretion of CSF, but also to absorb heavy metals and thereby at as a barrier to protet the brain (11, 23, 673

11 C. WANG ET AL. 52). In the pituitary, uptake of Mn has been reported in animals (68, 35, 36, 4), and prolonged postdosing retention within the pituitary has been noted (6,8,36,4). Thus, the uptake and prolonged retention of Mn in the pituitary seen in this study are onsistent with published data. Although treatment for 5 weeks with high doses of MnSO, (1 mgkg/day, subutaneously) has been shown to affet thyroid funtion in rats (6). Additional analysis of blood samples obtained from the infusion subjets during the 4day followup period, in the present study, showed no effet of either dose of mangafodipir on levels of thyroidstimulating hormone, triiodothyronine or free thyroxine. Furthermore, no symptoms related to possible altered pituitary funtion or neurobehavioural hanges have been observed in any patient given mangafodipir in linial Phase I1 and I11 studies, or in any of the nonlinial studies after subhroni or hroni treatment with high doses of mangafodipir (18, 19, 28). Mangafodipirindued MR enhanement was seen in some organs, and the time ourse and dosedependeny of the enhanement varied from tissue to tissue. It is lear from these results that mangafodipir may be potentially useful for ontrast enhanement in other organs in addition to the liver. Reports of preliminary linial experiene with mangafodipir in imaging the normal panreas (16, 27), diseased panreas (13), normal kidneys (14), and adrenals (34) have been published, as have results from studies on animals with hemially indued panreatitis (15). Fat has been a ommonly used referene in MR SI measurements but in the present study it was only applied to TlB images. The spinaleretor musle was seleted as the referene in T1A and T2A images, beause suffiiently large areas of fat for appropriate ROI plaement were not present in the images of all subjets. After i.v. injetion of MnCl,, at doses up to 25 pmolkg, the amounts of Mn found in fat and skeletal musle were so low that the TI relaxivity of adipose tissue and skeletal musle would not have been affeted (47). For all ROIs measured in abdominal tissues or organs, normalized mean baseline SI values before the first and seond dosings were virtually idential, further onfirming that using this musle as a normalization fator was valid. CSF has been proposed as a suitable referene by some authors (3,31), and from the results of this study we onsider it to be a stable and easytouse intensity referene that should be appliable in brain MR studies. In this study, as in previous linial studies, mangafodipir proved safe when administered as an infusion or bolus injetion, and the results are onsistent 674 with those from linial Phase I1 and I11 studies using similar doses and modes of administration. The only differene between bolus injetion and infusion was that bolus injetion resulted in transient, mild flushing whereas infusion did not. This was not surprising, as flushing has been ommonly seen after administration of the drug as a bolus injetion over approximately 1 min (1, 4, 21, 3, 41, 42, 44, 5 1). There was no measurable treatmentrelated ateholamine release in any subjet in this study or in nonlinial studies in dogs (25); it is, therefore, unlikely that the flushing and minor hanges in heart rate and blood pressure sometimes observed following injetion of mangafodipir are mediated through ateholamine release. It is diffiult to draw onlusions based on the pharmaokineti results obtained due to the omplexity of the metabolism resulting from the interation between mangafodipir and plasma Zn. Full details of the metabolism of mangafodipir and pharmaokinetis of the metabolites are presented elsewhere (49). That the halflife of the first elimination phase of Mn from plasma is short (<2 min) is most probably mainly due to the rapid uptake of Mn into different tissues, and partly due to the rapid initial renal elimination of Mn in the form of the mangafodipir metabolite MnPLED (9). The relatively long terminal plasma halflife of Mn ( h) is probably due to the redistribution of Mn from tissues into the plasma, and its subsequent elimination via the hepatobiliary system into the faees. That plasma onentrations of Zn derease after administration of mangafodipir is due to the displaement of Mn by Zn (transmetallation) in a large fration of the administered dose of mangafodipir, and the subsequent exretion of metabolites of ZnDPDP in the urine (9,49). Both the total plasma learane of Mn and the apparent volume of distribution are onsistent with the rapid and relatively extensive uptake of the Mn released from mangafodipir into tissues. The total plasma learane of Mn is more rapid than its renal learane, whih is lose to the glomerular filtration rate, and the volume of distribution indiates distribution outside the extraellular fluid. The nonlinear relationship observed between several pharmaokineti parameters and dose (i.e., inrease in AUC, redutions in CL and Vd,,, and subsequent inreased fe,urine of Mn that our with inreased dose) ould be explained by a redution in the relative degree of transmetallation of mangafodipir with inreased dose. It an be expeted that this would alter the subsequent kinetis of uptake of the released Mn into tissues, and lead to a nonlinear inrease in the SI of the abdominal organs, primarily the liver and the panreas, with inreased dose.

12 MR PROPERTIES AND PHARMACOKINETICS OF MnDPDP Sine Mn is an endogenous element with a slow biologial turnover (45) and it is expeted that some of the administered Mn would have entered into the normal body pools, full reovery of Mn was not expeted during a followup period of only 4 days. Inreasing the rate of administration of mangafodipir from an infusion to a bolus injetion would inrease the maximal plasma onentration of Mn without affeting any other pharmaokineti parameters of Mn and, therefore, probably not affet the effiay of mangafodipir. Conlusions The pharmaokinetis of mangafodipir are onsistent with a rapid and relatively extensive uptake of the Mn that is released from mangafodipir into tissues, and this is evident as ontrast enhanement within suh tissues. The most pronouned ontrast enhanement in the abdomen was seen in the liver, followed by the renal ortex, and the panreas. The enhanement lasted longest in the panreas, somewhat shorter in the liver and still shorter in the renal ortex. The spleen and the renal medulla were enhaned, but the enhanement was weak in the spleen and the timeintensity profile was irregular for the renal medulla. The enhanement was dosedependent and only apparent in the T1weighted images. There was no ontrast enhanement in the brain in tissues proteted by an intat bloodbrain barrier. Inreases in SI were seen in the horoid plexus and the pituitary gland, and the enhanement of these strutures was not dosedependent and prolonged. At a dose of 5 pmolkg b.w., 1 mm mangafodipir appears to be a useful agent for providing ontrast enhanement in various abdominal organs, and it allows a relatively long imaging window as near maximal ontrast enhanement lasts for several hours after administration. The overall safety of mangafodipir was good, and onsistent with that reorded in linial Phase I and I1 studies. 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