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2 J. Pharm. Pharmaol. 1995, 47: J. Pharm. Pharmaol. Reeived Marh 15, 1995 Aepted July 20, 1995 Frusemide and Its Ayl Gluuronide Show a Short and Long Phase in Elimination Kinetis and Pharmaodynami Effet in Man TOM B. VREE++, MAGDALENA VAN DEN BIGGELAAR-MARTEA* AND CORRÍEN P.W.G.M. VERWEY-VAN WISSEN* * Department o f Clinial Pharmay, and + Institute o f Anaesthesiology} Aademi Hospital Nijmegen Sint Radboud, Geert Grooteplein Zuid 8, 6525 GA Nijmegen, The Netherlands Abstrat The pharmaokinetis of 80 mg frusemide given orally were investigated in normal subjets using a diret HPLC method for parent drug and its ayl gluuronide onjugate. Two half-lives ould be distinguished in the plasma elimination of both frusemide and its onjugate, with values of 1-25±0-75 and 30-4zb 11*5h for frusemide and 1-31 ±0*60 and 33*2±28*0h for the onjugate. The renal exretion rate-time profile showed two phases; the rapid elimination phase lasted from 0-15 h and the seond and slow phase, from h. During the first 15 h, 33 '3 ± 4*8% of the dosed frusemide was exreted; in the remaining period h, 4'6 ± 1*5% was exreted. In the same two periods the exretion of the gluuronide was 13*4 ±4*7 and 1*9 ± 1*1%, respetively. The mean renal learane of frusemide was 90-2± 16 9 mlmin-1 during the first period and 91*5 ± 29*3mLmin 1 in the remaining period, during whih the stimulation of urine prodution was absent. The renal learane of the ayl gluuronide was 702 db 221 mlmin 1in the first period, but only 109 ± 51 *0 mlmin 1in the seond period. The stimulated urine prodution in the first 6h after administration amounted to 2260 ± 755 ml (measured urine prodution minus baseline value of I mlmin-1 (360 ml). During the seond or rebound period (6-96 h after drug administration), the quantity of urine was 990 ± 294 ml lower than what would lave been expeted from the baseline prodution of 5400 ml, This redued prodution (0-82mLmin"1) is equivalent to an 18% redution in the average urine flow rate of 1 mlmin-1. Frusemide (4-hloro-Af-(2 furylmethyl)-5-sulphamoylanthranili aid, pka 3*9) inhibits the ative reabsorption of hloride ions in the thik asending limb of the loop of líenle by binding to one of the Cl- binding sites of the NaH/ 2C1 /K+ o-transport system. In man, frusemide is metabolized to its ayl gluuronide (Beerman et al 1975, 1977). Ayl gluuronides are unstable in alkaline media (ph > 7*0); therefore, for analysis urine must be kept aidi at ph 5*0 in order to prevent hydrolysis and isomerization of ayl gluuronides even before exretion (Faed 1984; Rahmel et ai 1985; Vree et al 1992a, 1993a, b). The reported half-lives (ti) of frusemide and its gluur- onide are of the order of 2h (Hammarlund et al 1985; Vree et al 1994, 1995b). In a pilot experiment in our laboratory, a seond, long half-life of frusemide and its ayl gluuronide beame visible (Vree et al 1994). Hammarlund et al (1985) mentioned the effet of an aute tolerane to frusemide s effet as being a homeostati adaptive response to the aute loss of salt or water. This homeostati response, whih Reyes alled a rebound effet (Reyes 1991), may also be the result of a prolonged disposition of frusemide at the Cl- binding sites. The aim of this investigation was to study the pharmaokinetis of frusemide and its ayl gluuronide in healthy volunteers, to assess the long half-life of parent drug and gluuronide onjugate, and to analyse the diureti and antidiureti response. Correspondene: T. B. Vree, Department of Clinial Pharmay, Aademi Hospital Nijmegen Sint Radbóud, Geert Grooteplein Zuid 8, 6525 GA Nijmegen, The Netherlands. Materials and Methods Drugs and hemials Frusemide and Lasix (40 mg tablets) were obtained from Hoehst (Amsterdam, Netherlands and Frankfurt, Germany). All other reagents were of analytial grade and obtained from Merk (Darmstadt, Germany). Frusemide ayl gluuronide was isolated and identified in human urine after administration of 80 mg frusemide (Vree et al 1994). Subjets Seven human subjets (4 males (non-smokers), 3 females (one smoker), mean age 34 ±7 years, mean bodyweight 80 ± 6 kg) partiipated in the study. The volunteers took 80 mg frusemide orally (as Lasix) after an overnight fast. The study had the approval of the hospital ethis ommittee, and informed onsent was obtained from the volunteers. Sampling Fingertip blood samples (2mL), obtained with Monolet lanets (Monojet, St Louis, USA), were olleted in heparinized Eppendorf vials (2 ml) at regular time intervals during 72 h following drug administration. After entrifugation, plasma samples were stored at -20 C pending analysis. Urine was olleted upon untimed voiding. The total time of sample olletion was 96 h. Urinary ph was kept aidi (ph 5*0-5-5) by the oral intake of 1 g ammonium hloride four times per day (Ammonhlor, Siidmedia, Munih, Germany). Four urine samples of 5mL from eah void

3 MUJSEMIDli ELIMINATION KINETICS AND PHARMACODYNAMICS 965 were immediately stored at -20"C pending analysis. Total Amion Miropartition system MPS-1 (Grae BV, Amio sampling time of urine was 96 h. Division, Capelle aan de IJssel, The Netherlands). The Eah urine void ( ml) was followed by ingestion average protein binding (is.d.) was alulated from two of 100 ml water during the first period of 6h. plasma samples from eah volunteer obtained at maximal plasma onentration, 1-2 h after administration. No aspe- Drug analysis iii drug binding to the filters was observed. Frusemide and its ayl gluuronide were assayed by HPLC as reported elsewhere (Vree et al 1994). The limit of quantitation of frusemide in plasma was 7 ngml 1, and for the Curve fitting was arried out (r2 >0*97), and the pharma Data analysis gluuronide 10 ngml-'1. The limits of quantitation in urine okineti parameters of the plasma onentration-time were 100 and 150 ngml 1 for the parent drug and gluur- urves, renal exretion rate-time profiles, and urine flowtime profiles were alulated using the MediWare omputer onide, respetively. The intra- and interday variation of frusemide and program (Proost & Meyer 1992). Areas under the onentration-time urves (AUC) were determined by the linear gluuronide in plasma and urine was <5%. Reovery of frusemide after deproteinization of plasma was 91*5 ± 5-1 %, trapezoidal rule. Oral learane (CL0) and mean residene and that of the gluuronide was 85'5d:4*7%. time (MRT) were alulated by standard methods (Proost & Plasma samples (100 / L) were deproteinized with 100 \CL Meyer 1992). aetonitrile and entrifuged at 3000#; 20 / L of the supernatant was injeted onto the olumn. The plasma samples alulated by dividing the amount exreted in the urine The renal learane during the appropriate period was were immediately injeted onto the olumn. A stability test during this period by the orresponding AUC value. Nonhas shown that the gluuronide was stable at ph 7*4 for only renal learane was defined as the oral learane minns the 30 min. renal learane. Urine samples were diluted with an equal volume of Reovery-, or rebound-time of the urine flow was defined water, and 20/ L of that mixture was injeted onto the as the time elapsed between the end of the urine flow olumn. The sample tray of the autosampler was proteted stimulation at whih the urine flow was < 1 mlmin^1 and from light. the time at whih the urine flow reahed again the value of > 1mLmin 1. Plasma binding Analysis of variane was arried out by standard proedures, and statistial differene was defined at P<0-05. The in-vivo protein binding of frusemide and gluuronide was measured in volunteer plasma samples by means of the Results t WH E u> _j -S a a o o o CD E t o CO Cl (D O X a) " r o a> DC 100-, 10-: 0. 1 T I b» t h... M l i n Mj... Frusemide Frusemide ayl 38.1% t1/ h gluuronide 1 5.0%... Frusemide Frusemide ayl gluuronide n r Time (h) Fig. 1. Plasma onentration-time urve and renal exretion ratetime profile of frusemide and frusemide ayl gluuronide in a representative volunteer after an oral dose of 80 mg frusemide. The long i\ti is visible in both the plasma and the urine urve. i Fig. I shows the plasma onentration-time urves and renal exretion rate-time profiles of frusemide and its ayl gluuronide in one representative subjet, in whih the slow elimination phase is visible in both the plasma and urine urves. Table I summarizes pharmaokineti parameters of frusemide in plasma and Table 2, the parameters in urine, Frusemide is quikly absorbed as an be onluded from the small values of tj8g, tmax, and t xa of absorption. The lag time in blood for frusemide is 0-29 ± 0* 16 h and of frusemide ayl gluuronide 0*32 ±0-24 h, (P=1*0). Both ompounds were also quikly exreted; the t[ag of the ompounds in urine do not differ signifiantly and did not differ from those in plasma. Two half-lives (a and 3) an be distinguished, in the plasma elimination of both frusemide and its onjugate. The t{a values of frusemide and its ayl gluuronide were 1 *25 =b0*75 and 1*31 ±0-60h, respetively, whih are not signifiantly different. The plasma onentration- and renal exretion rate-time urves run parallel, resulting in similar values of the alulated pharmaokineti parameters; plasma and urine t^ values of frusemide are respetively 33-2±28-0 and 29-7 ± 21*9 h. The orresponding values for frusemide ayl gluuronide are 30*4i 11 5 and 29*9 ± 2 0 2h. Although the long elimination half-life of frusemide and its ayl gluuronide in plasma was visible in five out of the seven volunteers, it was learly visible in the urinary exretion urves of all volunteers (29*7 ± 21 9 h, CV = 73*7%).

4 966 TOM B. VREE ET AL Table 1. Pharmaokineti parameters in plasma of frusemide (80 mg) (n = 7). Parameter Frusemide Ayl gluuronide P F 0*53 ±0*07 0*15±0 04 0*0003 tlag (h) 0-29 ±0*16 0*32 ±0-24 >0*80 C (h) 1*98 ± ±0-74 0*58 U I si ä v / Cmnx ((j,gml~[) 2*20 ±0*84 0*11 ±0*07 0*0156 I1 JH s\ >1 W * tbs (h) 0*30 ±0*26 0*68 ±0*50 0*034 l!a (h) 1-*25 ±0*75 1*31 ±0*60 0*47 + I X \ / % (h) 33*2 ±28*0 30*4 ±11*5 1*00 MRT ih) 10-2 ± *8 ±15*9 0*81 CL0 (mlrnin-1) 131 ±26-5 CLr (mlmin-1) 1 \ M W 0-15 h 90*2 ± ± h 91*5 ±29*3 109 ±51-0 CLnr (mlmin!) 0-15h 41*0± 16* h 32*1 ±19*6 VdM(L) 21-9 ± 12*3 94*8 ±68* Exreted (% dose) 0-15 h 33*3 ±4*8 13*4 ± 4*7 < h 4*6 ± 1*5 1*9 ± 1*1 < 0*0001 Protein binding (%) 98*0 ±2*0 96*1 ±2*0 0*0284 P differene between frusemide and its ayl gluuronide. The large oeffiient of variation was aused by two volunteers showing extremely long half-lives of 37*8 h and 73-7 h (mean 55*8 ± 25*4 h; CV = 45.5%). The other five volunteers showed a muh more onsistent half-life of 16*4rL 1*94h (11-8%). For frusemide ayl gluuronide the mean half-life in urine was 29*9 ± 20*2h (67*6%). The great variation was aused by three volunteers showing long half-lives of 37*8, 54*4, and 58*6h (50*3±11*0h; 21*9%). The other four volunteers showed a relatively short half-life of 14*6 ± 2-63 h (18-0%). Protein binding The protein binding of frusemide (98-0 ±2*0%) is signifiantly higher than that of the ayl gluuronide (96* 1 ± 2*0%, P = 0*0284). Perentage of the dose exreted in the urine The main ompound in the urine was frusemide. The renal exretion rate-time profile showed two phases, the rapid elimination phase lasting from 0-15h, and the seond, slow phase from h, During the first 15 h, frusemide exreted aounted for 33*3 ±4*8% of the dose; in the remaining h period, 4*6 ±1*5% was exreted. In the same two periods, the perentage frusemide ayl gluuronide exreted was 13*4±4*7%, and 1*9±1*1%, respetively. In total, 46*7 ± 8*3% was exreted during the first 15h, and 6-4 ±2*1% during the remaining h period. During the entire period (96 h), 53*0 ±7*2% of the dose was reovered from the urine. Renal learane The mean renal learane of frusemide was alulated for the two elimination phases and was found to be 90*2± 16*9mLmin~l during the first period (0-15h), and 91*5±29*3mLmin~t during the remaining h period, Table 2. Pharmaokineti parameters in urine of frusemide (80 mg) (n ~ 7). Parameter Frusemide Ayl gluuronide P tb* (h) 0*20 ±0-17 0*42 ± 0*24 0*068 (h) 0*86 ±0*51 1*19 ± 0*44 0*24 Umax Qig min"1) 177 ±34*0 92*6 ±36*5 0*0007 ^abs (h) 0*32 ±0*34 0*37 ±0*42 0*80 (h) 1*23 ± 0*47 1 *45 ± 0*51 0*35 % (h) 29*7 ± 21 *9 29*9 ±20*2 > 0*8 MRT (h) 11*1 ±10*4 11 *7 ±7*9 > 0*8 Exreted (%) 0-15 h 33*3 ±4*8 13*4 ± 4*7 < 0* h 4*6 ± 1*5 1 *9 ± M 0*0018 < Total exreted (%) 0-15 h 46*7 ±8* h 6*4 ±2*1 0*0001* 0-96 h 53*0 ±7*2 0*15** P differene between frusemide and gluuronide; *between 0-15h and h; **between 0-15h and 0-96h. *Change between initial and final elimination in the urine profile.

5 FRUSEMIDE ELIMINATION KINETICS AND PHARMACODYNAMICS 967 Table 3. Mean urinary diuresis parameters of frusemide (80 mg) (n = 7). Parameter Mean ± s.d. P Diuresis tiag (h) 0*18 ± 0T9 U * (h) 0-77 ± Umax (mlmin-1) 21*3 ± 6*1 ti (h) 0-76 ±0*26 MRT (h) 2*59 ±0-82 telïet (h) 5*5 ±0-5 ^re bound (h) 64-7 ± 14-4 Urine prodution (ml)* 0-6 h *0 ± ** 6-96 h -990*0 ±294 *Urine prodution exeeding the baseline value of 1 ralmin"1. **P value, differene between the two periods of urine prodution. teff?t, trbound, time ourse of the effet. Umnx maximal urine prodution. in whih there was no stimulation of urine prodution. The learane values in both periods were similar (P> 0*8) (Table 1). The renal learane of the ayl gluuronide was 702 ± 221 mlmin-1 in the first period but signifiantly dereased to 109 ± 51*0 mlmin-1 in the seond period (P = 0*0083). Urine prodution The stimulated urine prodution in the first 6 h after administration amounted to 2260 ± 155 ml (measured urine prodution minus baseline value of 1 mlmin 1 (360mL) (Table 3). During the seond or rebound period of 6-96 h after drug administration the average urine prodution was 990±294mL lower than what would have been expeted from the baseline prodution of 5400 ml. This redued prodution is equivalent to an 18% redution in the baseline urine flow rate of 1 mlmin"1(0*82 mlmin-1). The reovery- or rebound-time of the urine flow lasted 64-7 ± 14*4 h (CV = 22*3%). Table 4 ompares the plasma onentration and renal exretion rates of frusemide and its gluuronide at the onset and end of stimulation of the urine prodution. Pharmaokinetis Disussion This study shows that frusemide and its ayl gluuronide exhibit two half-lives. The short half-life of approximately 2 h is well known and related to the pharmaodynami effet of the stimulation of the overall urine prodution. The seond half-life of approximately h has not been reported previously. During this slow elimination phase, only 4*6 ± 1-5% of the administered dose is exreted, whih is 14% of the amount exreted during the first 15 h. During the first phase, 13*4% of the ayl onjugate is exreted, and during the seond phase, only 1*9 ±1*1%, whih is 14% of the first phase and the same perentage reported for frusemide. The short t}a values of frusemide and its ay! gluuronide in plasma give rise to the assumption that both ompounds are exreted by glomerular seretion plus ative tubular seretion. Indeed, the apparent renal learane of frusemide was 90mLmin 1, whih is similar during the first and seond phases of elimination. The apparent renal learane value of the ayl gluuronide is high during the first phase (0-6 h; 702 ± 221 mlmin-1) and lower in the seond phase (109 ± 51*0mLmin"1). In the seond phase, the renal learane values of frusemide and its ayl gluuronide are similar. The extreme high renal learane of the ayl gluuronide during the first phase may be the result of hepati and renal formation of the gluuronide (Smith & Benet 1983; Vree et al 1992a, b); the latter eased in the seond phase of the elimination. Probeneid inhibits the renal learane of both frusemide (Chennavasin et al 1979; Smith et al 1980; Vree et al 1995b) and its ayl gluuronide (Vree et al 1995b). The relation between stimulation of the urine prodution and the renal formation of the ayl gluuronide may be oinidental, or it may indiate that the pharmaodynami effet is the result of the ation of the renal ayl gluuronide. Onset and offset o f the effet The pharmaodynami ativity of frusemide is believed to be produed as follows. The ompound passes the kidney (in the thik asending part of Henle s loop), until its onentration or exretion rate reahes 21 ^gmin-1 (Koajarern et al 1982); the reabsorption of the Cl" ions is inhibited, resulting in a derease in water reabsorption and inrease in overall urine flow. Indeed, as soon as frusemide and its ayl gluuronide appear in the urine after a similar lag time, the urine flow inreases. Table 4 shows that in our group of subjets, a frusemide renal exretion rate of 28*0 ± 2*9 (Mg min-1 (10*4 %CV) in the Table 4. Comparison of the urine flows, plasma onentrations, and renal exretion rates of frusemide and frusemide ayl gluuronide at the onset and end of the effet (mean ± s.d.) (n = 7). Parameter Start/onset End Urine flow (mlmin-1) Plasma Frusemide ( gml-1) Ayl gluuronide (/ig ml 1) Urine Frusemide (fig min-1) Ayl gluuronide ( igmin-1) 8*04 ±4* ±0* *06±0*45 0*44 ± 0 T *059 ±0*062 0*046 ±0* *9 ±58*1 28*0 ±2*9 0* *9 ± 14*2 19*0 ± 10*8 0*5039

6 968 T0M B- VREE ET AL elimination phase of the kineti urve is orrelated with the end of the stimulation of the urine prodution. The orresponding exretion rate of the ayl gluuronide is 19-0 ± 10*8/ gmin 1 (CV^56*8%). During the onset of the pharmaodynami effet, the proesses our muh faster, produing a larger oeffiient of variation. For the first urine sample, the average urine prodution is already 8-0 ±4-6 mlmin"1(57*5%) with a frusemide exretion rate of 62-9±58-l pgmin-1 (92-6%) and an ayl gluuronide value of 14*9± 14*2//gmin 1(94*8%). Strikingly, the pharmaodynami effet starts and ends with exretion rates for the ayl gluuronide that do not differ (P = 0*50). The large differene and oeffiients of variation of the exretion rates of frusemide in the first urine sample and onset of the pharmaodynami effet makes the differene between onset and end of effet not statistially different. Similar data an be derived for the plasma onentration of parent ompound and metabolite and the start and end of the urine flow stimulation (Table 4). A great differene is observed between frusemide plasma onentration at onset and end of the urine flow stimulation (P ). This is not observed for the frusemide ayl gluuronide for whih the onentrations are not signifiantly different (P = 0.55). The stimulation of the urine prodution faded (< 1mLmin 1) when the renal exretion rate of frusemide drops below the threshold of 20 gmin 1, as reported by Koajarern et al (1982). During the absorption phase, this value was already ahieved in the seond urine sample within 1 h of oral administration. The onset looks like an instantaneous maximum effet for an 80-mg dose. the total time of urine flow stimulation plus reovery time was 6h + 65 h = 71 h (3 days). The reported 24-h reovery period reported by Reyes (1991) was based on a olletion period of only 24 h. During this reovery period, frusemide and its ayl gluuronide were slowly eliminated from the body with a long half-life of h for this phase. This reovery period was named aute tolerane to frusemide diuresis in man (Hammarlund et al 1985); rebound effets were named by Reyes (1991). This reovery or rebound period oinides with the t^ of h for both frusemide and its ayl gluuronide. The rebound effet may be the result of a biphasi effet of frusemide or its ayl gluuronide. In onentrations or renal exretion rates > 20 gml 1, there is a stimulation of the urine prodution, while at onentrations below this threshold there exists an inhibition of the urine prodution. These low renal exretion rates may exist in the slow elimination phase after administration of a therapeuti dose of mg or higher dose, or they an be obtained after administration of 5 mg frusemide four times a day. The urine prodution under this low frusemide dosing regimen should be ompared with baseline values of urine prodution in eah patient or volunteer. When this was arried out in a pilot experiment, no inhibition of urine prodution was deteted. Clinial impliedtions Cumulation of the frusemide plasma onentrations, due to the slow elimination phase, and umulation of the rebound or reovery phase may indue a braking of the therapeuti or pharmaodynami effet (Brater 1991), Rebound The pharmaodynami effet-time urve shows a biphasi harater. First, there is binding to one of the Cl~ binding sites of the Na+/2C1 /K+ o-transport system of the thik asending part of the loop of Henle, resulting in an inrease of the urine prodution greater than 1mLmin 1(Greger & Shlatter 1983; Wittner et al 1991; Swan 1994), A rebound phase follows in whih the urine prodution is less than the baseline value of 1mLmin"1. During the pharmaodynami effet, 2260 ± 755 ml was exreted above the baseline value of 1 mlmin 1 for the unmediated and well-hydrated subjets. Despite the fat that the subjets maintained their normal drinking and eating patterns, during this exess urine exretion period, it took three days for the body to regain this amount of fluid. The average urine prodution over those three days was 990 ± 294 ml less than what would have been exreted with the baseline value of 1mLmin 1. The baseline urine prodution of 1 mlmin 1(= 1440mL in 24) was taken as a onservative estimate; the subjets showed values of 1-2mLmin 1in other long-lasting pharmaokineti experiments with naproxen (Vree et al 1993a, b) and sulphamethoxazole (Vree et al 1995a). This time ourse of the rebound effet was subjetively felt to be three days, as experiened by the same subjets in other, short-term, frusemide experiments (Vree et al 1995b). 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