Effect of fenoldopam in dogs with spontaneous renal insufficiency

European Journal of Pharmacology, 184 (1990) 195-199

195

Elsevaer EJP 20674

Short communication

Effect of fenoldopam in dogs with spontaneous renal insufficiency D a v i d P Brooks, R o b i n G o l d s t e l n , Paul F K o s t e r , P. D e n n i s D e P a l m a , M a r t i n D i C n s t o , Krlsten Karplnslo and Marty Hyneck Departments of Pharmacology, lnvestlgatwe Toxtcology and Drug Metabohsm, SmtthKhne Beecham Pharmaceuticals, Kmg of Prussza, PA, USA

Received 5 April 1990, accepted 12 June 1990 Fenoldopam adrmmstratlon orally or 1v resulted m slgmhcant increases m paraanunohlppunc acid (PAH) clearance m both four control dogs and four dogs with chromc renal fadure Oral fenoldopam resulted m significant plasma levels of fenoldopam sulfate metabohtes One metabohte, fenoldopam-8-sulfate, a potentml lntubttor of orgame amon transport, dM not depress renal cortical shce accumulation of PAH The data therefore indicate that m dogs vath chronic renal failure, PAH clearance after fenoldopam admlmstratlon Is a rehable measure of renal plasma flow, and fenoldopam can result m an increase m renal plasma flow Fenoldopam, Renal fadure (chromc), Renal blood flow, (Dog)

1. Introduction Fenoldopam ( S K & F 82526-J) is a dopamlne agomst with renal vasoddator properties In dogs, rats and man, fenoldopam results in slgmflcant increases in renal blood flow and decreases in renal vascular resistance (see Ackerman et al, 1982, and Lokhandwala, 1987 for reviews) The effects of fenoldopam on renal blood flow in chromc renal failure, however, are unknown In the present study, therefore, we have investigated the renal effects of fenoldopam in normal dogs and dogs with spontaneous chromc renal failure

2. Materials and methods 2 1 In vtvo studtes

Four young adult mongrel dogs (10 6-16 4 kg; three male, one female) with chmcal indications of

Correspondence to D P Brooks, SrmthKlme Beecham Pharmaceutacals, Department of Pharmacology, L521, P O Box 1539, King of Prussta, PA 19406-0939, U S A

chromc renal failure (plasma creatlmne concentration > 1 5 m g / d l ) were used in these experiments Chromc renal fadure was identified by routine screening, and in two animals in which renal tustology was performed the renal failure appeared to be due to either congenital nephrosclerosls or as a result of an infection These ammals and four control young adult male dogs were placed on a low protein diet (mammum 3 5% crude protein, camne K / D prescription dlei, Hill's Pet Products, Topeka, KS) at least 3 weeks before study Serum creatlnme concentrations on the low protein diet were 2 5 2 _ 0 74 (1 6-4 7) m g / d l for the chronic renal fatlure dogs and 0 94 + 0 09 (0 81 2) m g / d l for the control dogs The dogs were tramed to stand quietly in a shng Food was withdrawn 17-18 h before the tests The urinary bladder was catheterized for unne collection and an mdwelhng catheter was inserted into a cephahc vein for continuous infusion of agents used to determine clearance rates A saphenous vein was cannulated for withdrawing blood samples. A prlrmng dose of paraarmnobappurlc acid (PAH, 2 5 m g / k g 1 v ) was administered and P A H then infused (dose adjusted appropnately to renal function) in sahne at a rate of

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196 0 02 m l / k g per mln After 80 m m of equihbratlon, two 20 m m clearance periods were obtmned Data from these two clearance periods were averaged to give a baseline value Immediately after these control clearance penods, fenoldopam was adrmmstered (randomly) as either an 1.v infusion (0 5 g g / k g man and 0 1 m l / k g nun) or orally (10 m g / k g ) m a gelatin capsule After 30 man, an additional four 20 man clearance periods were evaluated Blood samples (5 ml) were collected at the madpoint of each clearance period Blood was centnfuged and the plasma assayed for PAH, endogenous creaUnme, fenoldopam and fenoldopam sulfate U n n e samples were assayed for PAH, creatamne and sodium The clearances of P A H and creatlmne were calculated using standard formulas Throughout the experiment, blood pressure was momtored either ind:rectly using a D y n a m a p or darectly from a Vascular-Access-Port T M or a carotid loop Vascular-Access-Ports T M were inserted and carotid loops constructed at least 1 month prior to the experiment under stenle conditions 2 2 Chemtcal analyses

Creattmne and sodium were analyzed using an autoanalyzer (Instrumentation Laboratory, System 508) P A H was analyzed using the method of Bretton and Marshall as modified by Srmth et al (1945), and fenoldopam and fenoldopam sulfates (fenoldopam-7-sulfate, fenoldopam-8-sulfate) by ingh performance h q m d chromatography with electrochermcal detection (Boppana et al, 1989)

the effects of fenoldopam-8-sulfate on P A H transport in vitro Renal cortical shces ( - 0 3-0 4 m m thick) from naive dogs were prepared free-hand, and were incubated :n a phosphate buffered medium (pH = 7 4 ) contalmng 10 m M lactate and 75 # M [3H]PAH (0 1 /tC1/rnl, New England Nuclear, Boston, MA) Fenoldopam-8-sulfate was added to lncubat:on media in various concentrations winch were comparable to or exceeded peak plasma concentrat:ons of fenoldopam-treated dogs Incubations were conducted at 25 or at 37 ° C for up to 90 nun, under a gas phase of 100% 02 Following incubation, tncholoracetlc acM digests of the shces and a 2 0 ml ahquot of the incubation medium were prepared and assayed for rachoact:v:ty Accumulation of P A H was expressed as a shce-to-medlum ( S / M ) ratio where S = d p m of :on per gram wet weight of tissue and M = d p m of 1on per mllhllter of incubation medium 2 4 Stattsttcal analyses

D a t a are expressed as means + S E M In VlVO data were analyzed using paared Student's t-tests The tune course of the responses to oral fenoldop a m vaned between dogs Therefore, all data for both oral and : v fenoldopam were calculated using the clearance period corresponding to the m a x i m u m change in renal plasma flow In wtro data were analyzed by a general hnear model procedure A P < 0 05 was used as a c n t e n o n of statistical sigmficance

2 3 In ottro studtes

3. Results

Since fenoldopam m dogs and humans is excreted m the unne primarily as fenoldopam sulfate and several sulfate esters are known to be transported by the renal orgamc anion (PAH) system (Curtis et al, 1974), it is poss:ble that fenoldopam sulfate may be transported into the pro:areal tubular cell by a sin~lar mechamsm Tins nught result m incomplete extraction of P A H by the lodney and underestimate drug-reduced changes m renal plasma flow when measured by P A H clearance Therefore, experiments were designed to evaluate

3 1 In vtvo studtes

Prehmlnary studies in dogs indicated that creatimne and P A H clearances remaaned stable throughout the infusion of vehicle in both control dogs and dogs with chromc renal fatlure Adrmmstratlon of fenoldopam either : v or orally resulted in slgrnficant increases in P A H clearance (fig 1) Desp:te large differences in basehne P A H clearance between normal and chromc renal failure dogs, the maximal % increase was s:rmlar for both

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total metabohtes to fenoldopam after x v and oral fenoldopam was 3 1 + 0 6 and 173 _+ 69, respectively

A

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i 33±10

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34+10

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Fenoldopam-8-sulfate (7 5-300 tam) did not affect PAH accumulation m dog renal cortical shces at either 25 or at 37 ° C In contrast, probemcxd, a classical inhibitor of the renal organic amon transport system, reduced PAH S / M ratios from 3 42 + 0 2 1 to 1 8 3 _ + 0 1 3 at 2 5 ° C and from 4 3 1 + 123 to 168_+0 at 3 7 ° C following 90 mln of incubation

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ILl O

4. Discussion n0

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0 BASELINE (ml/mm)

NORMAL 30±8

CRF 12±3

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Fig 1 Effect of fenoldopam on PAH (CpAH, upper panel) and creatamne (CcRF_AT, lower panel) clearances m control and CRF dogs * P < 0 05, * * P < 0 01 vs basehne

groups (approximately 100%, fig 1) Fenoldopam by either route of admlmstratlon tended to increase creatxmne clearance as much as 25-50%, however, these values were not statistically slgmficant from basehne values m any of the groups (fig 1) Urinary sodium excretion, unne flow, mean arterial blood pressure and heart rate were not affected slgmficantly by fenoldopam m any of the groups (data not shown) I v fenoldopam generated steady state plasma concentrations of drug ranging from 4 to 10 n g / m l Plasma concentrations of fenoldopam sulfate ranged from 4 to 40 n g / m l following i v fenoldopam in both normal and chromc renal failure dogs (fig 2) Oral fenoldopam resulted m variable peak plasma concentrations of fenoldopam (6-300 n g / m l ) and significantly tugher plasma levels of fenoldopam sulfate (from 2 000 to 15 000 n g / m l ) than after i v fenoldopam The raUo of

Stimulation of dopamlne D 1 receptors by fenoldopam results in slgmflcant increases in renal blood flow and decreases in vascular resistance in a number of species including man (Lokhandwala, 1987) Fenoldopam has beneficial effects m hypertension and congestive heart fadure due to its cardiovascular and perhaps renal effects (Lokhandwala, 1987) The present study indicates that fenoldopam administered either 1 v or orally resuits m a significant increase in PAH clearance in dogs wtth chromc renal fadure (renal function approxamately 1 / 3 of normal) The increases in PAH clearance were not accompamed by staustically significant increases m creatmlne clearance Thus, there was a significant fall m filtration fraction, indicating that fenoldopam is hkely causing predomanantly efferent artenolar vasoddaUon The 100% increase m PAH clearance induced by fenoldopam indicates that there is considerable renal reserve in dogs with chronic renal failure Preliminary studies in both the normal dogs and the dogs with chromc renal failure indicated that there was good correlation between the clearance of muhn and the clearance of creatlmne This suggests that at least in the dog, endogenous creaumne clearance is a useful method for studymg glomerular filtration rate F e n o l d o p a m , on oral adminlstrat~on, is metabohzed primarily to sulfate conjugates These sulfate conjugates could competmvely inhibit tub-

198 RATIO = 173-+69 25

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0025 FENOLDOPAM

TOTAL SO4 METABOLITES

FENOLDOPAM =v (0 5 ug/kg mln)

FENOLOOPAM

TOTAL SO4 ME T A B O L I T E S

FENOLDOPAM p o (10 mg,kg)

Fig 2 Mean and lndlvadual plasma levels of fenoldopam and total sulfate metabohtes of fenoidopam m control and CRF dogs Values represent the plasma concentrattons associated w]th the peak changes m PAH clearance

ular orgamc amon (PAH) transport leading to an underestimate of renal plasma flow. However, the m vitro data reported hereto indicate that the sulfate metabohte of fenoldopam did not alter PAH accumulaUon by dog renal cortical shces, suggesting that PAH and fenoldopam sulfate do not share a common transport mechamsm Thus, PAH clearance ~s hkely to be a good estimate of renal plasma flow m the presence of this metabohte

Fenoldopam did not have any effect on sodmm excretion m either normal dogs or dogs with chromc renal fadure Ttus is m contrast to some previous observations m dogs (Ackerman et al, 1982; Jose et al, 1987, Lokhandwala, 1987), but slrmlar to that reported by Hddltch et al (1988), indicating that the natnuret~c response to fenoldopam m dogs is variable and may depend on the experimental preparation It is unhkely that lugher doses of fenoldopam would have been

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natrmretxc since exqdence suggests that the natnuretlc effect of fenoldopam occurs at doses lower than that required to increase renal blood flow (Hedge et al, 1989) In normal as well as hypertensive subjects, fenoldopam appears to be natnuretlc (Lokhandwala, 1987, Murphy et al, 1987) In summary, this study indicates that fenoldop a m gwen i v or orally results in s~gnlhcant increases m renal plasma flow m dogs w~th chromc renal failure This raises the posslblhty that fenoldopam may have therapeutic utthty m chronic renal faxlure

Acknowledgements We gratefully acknowledge T McDonough for perforrmng the sodium, creatmme and PAH assays, D A Federowlcz and M Cyronak for the fenoldopam assays, and S Tim and L Contmo for expert assistance in preparing the manuscript

References Ackerman, D M , J Wemstock, V D Wiebelhaus and B Berkowltz, 1982, Renal vasochlators and hypertension, Drug Dev Res 2, 283 Boppana, V K , K M Dolce, M J Cyronak and J A Zlemmak,

1989, Slmphfied procedures for the deterrmnatlon of fenoldopam and ItS metabohtes m human plasma by tughperformance hqmd chromatography w~th electrochemical detecuon compartson of manual and robouc sample preparation methods, J Chromatogr 487, 385 Curtis, C G , D J Hearse and G M Powell, 1974, Renal excreUon of some aryl sulphate esters m the rat, Xenoblottca 4, 595 Hedge, S S, A Raccl, F Amenta and M F Lokhandwala, 1989, Evxdence from functional and autoradlograpluc studles for the presence of tubular dopamane-1 receptors and their mvolvement m the renal effects of fenoldopam, J Pharmacol Exp Ther 251, 1237 Hddltch, A , K L Clark, M J Robertson and G M Drew, 1988, Effects of the selecuve dopanune DA 1 receptor agomst fenoldopam on renal funcUon m the anaesthet~sed dog, Br J Pharm 95, 858D Jose, P A , G M Eisner and J E Roblllard, 1987, Renal hemodynarmcs and natnuresls induced by the doparmne-1 agomst, SK&F 82526, Am J Med Sc~ 294, 181 Lokhandwala, M F , 1987, Prechmcal and chmcal studies on the cardiovascular and renal effects of fenoldopam a DA-1 receptor agomst, Drug Dev Res 10, 123 Murphy, M B, C E McCoy, R R Weber, E D Fredenckson, F L Douglas and L I Goldberg, 1987, Augmentation of renal blood flow and sodmm excretion m hypertensive paUents during blood pressure reducuon by intravenous adrmmstrauon of the dopamlne 1 agomst fenoldopam, Circulation 76, 1312 Srmth, H W , N Fmkelstem, L Almunosa, B Crawford and M Graber, 1945, The renal clearances of substttuted luppunc actd denvatwes and other aromatic acids m dog and man, J Chn Invest 24, 388