Cardiovascular effects and pharmacokinetics of the carboxylic ionophore monensin in dogs and rabbits

Life Sciences, Vol. 29, pp. 1959-1966 Pergamon Press Printed in the U.S.A.

CARDIOVASCULAR EFFECTS AND PHARMACOKINETICS OF THE CARBOXYLIC IONOPHORE MONENSIN IN DOGS AND RABBITS

Mohammad Fahim and Berton C. Pressman

University of Miami School of Medicine, Miami, Fla 33101

(Received in final form September 9, 1981)

Summary

Monensin, a carboxylic ionophore, produces strong pressor, posit ive chronotropic effects and elevates the blood glucose level when injected intravenously (I00 ~g/kg) into pentobarbital anesthe- t ized dogs or administered ora l l y (2 mg/kg) to conscious dogs. In- travenously administered monensin disappeared from the blood rapidly with a t½ of ca. 2.5 min and,in the conscious dogs, ingested monensin showed a peak plasma level 90 min af ter feeding; this coin- t ided with the time of maximum increase in ar ter ia l blood pressure and blood glucose. In conscious rabbits, although higher doses of monensin were administered, 200 ~g/kg intravenously and I0 mg/kg o ra l l y , i t s cardiovascular effects were less than observed in the dog and were slower in onset. This correlated with slower clear- ing of injected monensin from the blood (t½ = 8 min) and slower entry of ingested monensin from the gut into the blood. Rabbit plasma and tissue levels were higher 17 hr af ter oral ingestion of monensin than six hr af ter ingestion.

The carboxylic ionophore monensin is a b io log ica l ly active metabolite, produced by Streptomyces cinnamonensis (4), which possesses ac t i v i t y against coccidia in chickens (16) and increases the ef f ic iency of conversion of feed to meat in cat t le (13). Accordingly, monensin is extensively used as a feed ad- d i t i ve for food producing animals, chicken and cat t le . I t has been reported that most of the ingested monensin is excreted in feces and very l i t t l e is found in urine and tissues of animals. These studies involved feeding labeled monensin to chickens (3H monensin) and steers (14C monensin) and measuring rad ioact iv i ty in the i r feces, urine and tissues (2,5,6). Using a th in- layer "bioautographic" assay for monensin in two separate studies, i t has been reported that in chickens fed monensin-supplemented feed for several days and purged for one day, there was no detectable amount of monensin in l i ve r , muscle and kidney (1,8). All these studies suggest that most of the ingested monensin clears from the body rapidly in feces and the t issue uptake is minimal.

Monensin produces strong cardiovascular effects when injected intravenously into anesthetized dogs (7,12,14,17). In small doses, i t produces a se- lect ive coronary vasodilatory effect and in large doses i t also produces pressor, posit ive chronotropic and inotropic effects (7,12,14). With the ex- ception of coronary vasodilatory response, a l l the other hemodynamic effects of monensin are mediated in part by release of endogenous catecholamines since they are attenuated by adrenergic antagonists or by pretreatment with reserpine (10,15,18). To date, most of the information concerning cardiovascular effects of monensin and other ionophores (9,10,11) has been provided by studies involv- ing intravenous in ject ion of the ionophore in the anesthetized dogs. Monensin

0024-3205/81/191959-08502.00/0 Copyright (c) 1981 Pergamon Press Ltd.

1960 Cardiovascular Effects of Monensin Vol. 29, No. 19, 1981

clearance and body uptake studies have been conducted on chickens and steers fed monensin-supplemented feed for several days (1 ,2 ,5 ,6 ,8) . None of these reports corre late the pharmacokinetic and pharmacological e f fects of monensin. Therefore, in order to establ ish the pharmacokinetic re lat ionships between o ra l l y ingested and intravenously in jected monensin, we determined plasma monensin levels in anesthetized dogs and conscious rabb i t s ,a f te r intravenous in ject ion,and in conscious dogs and rabb i t s ,a f te r oral administrat ion of monensin,by means of a sensi t ive radiochemical assay we have developed (3). In rabbi ts , t issue uptake of menensin in various organs was also determined. Ar ter ia l blood pressure, heart rate and plasma glucose levels were monitored.

Methods

Anesthetized dogs ( i . v . monensin): Mongrel dogs weighing 16 to 25 kg were anesthetized with sodium pentobarbi ta l , 30 mg/kg i . v . , and vent i la ted with room a i r using a posi t ive pressure resp i ra tor (Harvard Model 607-D). The a r te r ia l blood pH and gases were maintained in the normal range. Polyethylene catheters were introduced into femoral ar tery and vein for a r te r ia l pressure recording, co l lec t ing blood samples, and drug administrat ion, respect ively. The a r te r ia l pressure was measured with a pressure transducer (Statham P23Db) and heart rate was monitored from a lead I I electrocardiogram (EKG). The EKG and a r te r ia l pressure were continuously recorded on a Grass Model 79 recorder. Blood was col lected in heparinized tubes, centr i fuged, and plasma was removed for glucose and monensin measurement.

Conscious dogs (.oral monensin): Mongrel dogs weighing 15 to 18 kg were conditioned for four consecutive days to stand in a s l ing for three hr every day and accept food pe l le ts . On the f i f t h day, a s t e r i l e catheter (18.5 gauge, 12 inches long) was guided through a 17 gauge, 2 inch long needle (Band l-Cath) and introduced into the femoral ar tery , and the dog was then gently placed into the sl ing for constraint and support. Another polyethylene catheter was introduced into the vein for continuous sal ine dr ip during the experiment. The a r te r ia l catheter was connected to a pressure transducer and EKG leads ( I I ) were f ixed. The a r te r ia l blood pressure and EKG were recorded continuously; the heart rate was determined from EKG recordings. To co l lec t a r te r ia l blood samples, the catheter was momentarily disconnected from the transducer and blood was withdrawn into heparinized tubes. The to ta l amount of monensin (2 mg/kg) to be administered to the dog was dissolved in a small volume of ethanol and taken up by three or four food pe l le ts . The pe l le ts were dried and then fed to the dog, which accepted them without hesi ta t ion.

Conscious rabbits ~ i . v . monensin): Albino rabbits weighing 2.25 to 3.5 kg were constrained in a l uc i te box and, under local anesthesia, the central ear ar tery was cannulated fo r recording a r te r i a l pressure and co l lec t ing blood samples; drugs were administered through a catheter in the ear vein. The blood pressure was measured with a pressure transducer and heart rate was determined from a lead I I EKG.

Conscious rabbits (oral monensin): ( I ) Animals sacr i f iced s ix hr a f te r feedin 9 monensin. Experiments were performed on albino rabbits weighing 3 to 3.5 kg. Ar ter ia l pressure and lead I I EKG measurement as well as blood col lec- t ion were carr ied out as described above. The rabbits remained in the con- s t ra in ing box during the experiment. Monensin was fed to the rabbi t in one or two pe l le ts . Six hrs a f te r feeding monensin, rabbits were sacr i f iced and various t issues were col lected for the monensin measurements. (2) Animals sacr i f iced 17 hr a f te r feeding monensin. Albino rabbits weighing 2.8 to 3.2 kg were fed monensin in one or two pe l l e t s , and the animals were sacr i f iced 17 hr l a te r ; blood and t issue samples were col lected for assay of monensin.

Vol. 29, No. 19, 1981 Cardiovascular Effects of Monensin 1961

Monensin assay: Two g wet t issue is diced and then homogenized with a Polytron in 7 ml methanol containing 0, I N acet ic acid. The acet ic acid assures that the ionophore is in i t s protonated form so that i t s extract io~ from t issue l i p ids into methanol is uniform. The homogenate is held at 70~C for 5 min to fu r ther coagulate the t issue and then centr i fuged. The clear methanolic extract is removed (4 ml) and the cat ion- f ree, protonated monensin extracted into 3 ml heptane by shaking in a glass stoppered tube. A 2 ml a l i - quot of the heptane ext ract is then transferred to a I dram screw top vial con- ta ining 2 ml of 5 mM Ba(OH)2 with enough CAPS (Cyclohexylamino Propane Sulfon- ic Acid) buf fer to adjust the pH to 9.5. The buf fer also contains ~ I uCi 22Na + and lO-bM car r ie r NaCI. Af ter being capped and shaken thoroughly, the v ia ls are centr i fuged to clear the upper organic phase of a l l aqueous droplets and 1 ml of the organic phase transferred to a s c i n t i l l a t i o n v ial for counting (dimethyl POPOP-PPO in toluene). The 22Na+ found in the organic phase is an index of the amount of monensin present as i t s l i p id -so lub le sodium complex.

The re l a t i ve l y high concentration_Qf Ba 2+ in the 22Na + containing buf fer controls by competition the amount of ZZNa + forming non-specif ic l i p i d soluble ion pairs with t issue fa t t y acids which, unl ike monensin, prefer Ba z+ over Na +. Enough l i p i d components capable of ion pair ing or complexing Na+~re neverthe- less extracted from the t issue to raise the organic-solubi l ized ~ZNa + above background and consequently i t is necessary to run separate controls and re- coveries of known amounts of monensin with each t issue type. For plasma, the methanol extract ion step is not required. To 2 ml plasma, I ml 0 .1N acetic acid is added and the monensin is extracted d i rec t l y into 3 ml heptane. The subsequent procedure is the same as for the t issue extracts.

Results

Anesthetized do~s ( i . v . monensin) (Figure 1): Plasma monensin levels de- cl ined rap id l y with a t½ of ca. 2.5 min. Ten min fol lowing in jec t ion of i00 ~g/kg i t dropped to i ns lgn i f i can t levels. Ar te r ia l pressure rose markedly three min fol lowing in jec t ion , peaked at ten min and returned to normal at 90 min. Heart rate showed a more rapid response course; i t was higher one min post in jec t ion , peaked at f i ve min and returned to normal wi th in 30 min. Blood glucose was elevated three min fol lowing monensin in jec t ion , peaked at 90 min and remained high at 120 min when the experiment was terminated.

Conscious do~s (oral monensin) (Figure 2): Oral ly administered ionophore would be expected to be absorbed more Slowly, hence a larger oral dose, 2 mg/kg was chosen ~o compare against the 100 ~g/kg i . v . dose. This oral dose produced somewhat stronger pressor and chronotropic e f fec ts , and in keeping with the slower absorption k inet ics the e f fec ts were more delayed and prolonged. Appre- c iable plas~:amonensin appeared at 15 min, the f i r s t post feeding blood sample, and did not pea~ unt i l 90 min post feeding. Blood pressure was minimally raised at 15 min post feeding; both systolic and diastol ic pressure were sig- n i f icant ly elevated at 20 min (p = < 0.05), peaked at 90 min and remained strongly elevated 150 min post feeding when the experiment was terminated. Heart rate was signi f icant ly raised 20 min post feeding, peaked at 45 min, and returned to control values at 60 min. Blood glucose lagged behind the other parameters measured; i t was signi f icant ly raised 20-30 min post feeding, peaked at 90 min and was s t i l l twice the control value at 150 min.

Conscious rabbits ( i . v . monensin I (Table I ) : Since preliminary studies had indicated that the rabbit was somewhat less sensitive to monensin than the dog, the ionophore was administered at 200 ~g/kg. This species showed a pressor response to monensin within one min which abated within ten min. A more persistent chronotropic response was also observed. Monensin cleared the blood of the rabbit considerably more slowly than i t did in the case of the


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Fig. 1 Fig. 2

Fi 9. 1 The dissipation of the intravenously administered monensin (100 ~g/kg) from the plasma and i ts effect on arterial blood pressure, heart rate and plasma glucose levels in anesthetized dogs. Each point is the mean of values obtained from 10 dogs. In this and subsequent figures, bars indicate the standard deviation. Statistical significant differences, compared with before monensin values (0 min) by paired t - test , are indicated by * (P < 0.05) ; * * (P < 0.01) ; or * * * (P < 0.001).

F i~. 2 Plasma levels of monensin, glucose and changes in a r t e r i a l blood pressure and heart rate in conscious dogs a f t e r feeding 2 mg/kg monensin. Each point is the mean of values obtained from f i v e animals. * (P < 0.05~; ** (P < 0.01); or *** (P < 0.001).

dog; the t½ appears to be of the order of eight min.

Conscious rabbits (oral monensin) IFigure 3): Ingested monensin appeared in rabbit plasma considerably more slowly and to a lesser extent than in the dog. Significant levels required four hr to appear, and levels increased during the subsequent two hr. A definite minimal pressor effect occurred during the f i f t h hr. A small increase in pulse rate occurred two to four hr after ionophore ingestion, peaking at three hr. Plasma glucose rose noticeably at three to four hr, peaked at f ive hr and remained elevated at six hr.


Tissue levels of monensin in rabbi t : Despite i t s low s e n s i t i v i t y to monensin the rabbi t proved more convenient for determining organ d i s t r i bu t ion of administered monensin. Table I I shows the fate of monensin (200 ~g/kg) in a series of animals sacr i f iced ten min a f te r in jec t ion. Monensin was found in the heart, lung, kidney and brain and to a lesser extent in the l i v e r .

Two series of monensin fed rab- b i ts were conducted, sacr i f iced s ix hr and 17 hr a f te r dosing, respect ively (Table I I I ) . From the plasma levels i t is evident that monensin continued to be absorbed for a considerable time. Levels at 17 hr are somewhat higher than at s ix hr indicat ing that the rate of monensin absorption remained higher than i t s rate of e l iminat ion. D is t r i b - ution among the organs from o ra l l y dosed animals was considerably more uniform; the most conspicuous d i f f e r - ence was in the l i v e r , low in monensin shor t ly a f te r in ject ion and r e l a t i v e l y higher when assayed 6 or 17 hr a f te r oral dosage.

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Discussion Fig. 3

This study extends previous observations of the pressor and pos i t ive chronotropic ef fects of carboxyl ic ionophores in anesthetized dogs to o ra l l y dosed conscious dogs (12). The response of both cardiovascular parameters to monensin is greater in the dog than i t is in the rabb i t , however

iEffects of o ra l l y administered monensin (10 mg/kg) on the plasma glucose leve l , a r te r i a l blood pressure, heart rate and appear- ance of monensin in plasma in conscious rabbi ts. Each point is the mean of values obtained from six animals. * (P < 0.05); or • ** (P < 0.001).

TABLE I

Effects of Intravenous In ject ion of Monensin (200 ~g/kg) on Blood Pressure, Heart Rate and Plasma Monensin Level in Conscious Rabbits. Values are Mean ± S.D., N = 7.

Time Af ter Monensin In ject ion (min)

Plasma Monensin Ar te r ia l Blood Pressure Heart Rate (~g/ml) (mmHg) (Beats/min)

Systol ic D iasto l ic

- i0 0 i01 ± i0 76 ± 7 182 ± 8

1 1.30 ± 0.15 139 ± 13" 91 ± 10 207 ± 7*

i0 0.52 ± 0.i0 108 + II 81 + 8 216 + 9%

S t a t i s t i c a l l y s ign i f i can t di f ferences, compared with before monensin, are indicated by *(P < 0.05); or t (P < 0.02).


TABLE II

Residues of Monensin in Various Tissues after Intravenous Injection of 200 ug/ kg Monensin in Conscious Rabbits. Val- ues are Mean + S.D., N = 7.

TABLE I I l

Monensin Residues in Various Tissues of Rabbits 6 and 17 hr after Feeding 10 mg/kg Monensin. Values are Mean + S.D.

Tissue Monensin Level (~g/g) Tissue/ 6 hr after 17 hr after Plasma Monensin Monensin

Heart 1.05 + 0.25 (N = 6) (N = 6) Lung 1.25 ¥ 0.30 Kidney 1.30 ¥ 0.30 (~g/ml) (~g/ml) Liver 0.18 ¥ 0.05 Plasma 0.085 + .020 0.39 + 0.16 Brain 0.88 ¥ 0.20 (~g/g) (pgTg) Muscle 0. I0 T 0.05 Heart 0.40 + 0.20 0.65 + 0.30 Fat 0.01 ¥ 0.005 Lung 0.35 ¥ 0.20 0.35 ¥ 0.20

- Kidney 0,50 ¥ 0.25 0.30 ~ 0. i0 Liver 0.55 ¥ 0.30 0.70 + 0.35 Brain 0.40 ¥ 0.25 0.50 ¥ 0.27 Muscle 0.20 ¥ 0.06 0.25 T 0,12 Fat 0. I0 T 0.04 0.20 ¥ 0. i0

the latter species is more convenient for subsequent tissue assays.

Orally administered ionophore is predictably absorbed more slowly than when injected i .v . , hence larger oral doses were chosen to produce effects comparable to injected doses. In the dog the injected dose was 100 ~g/kg vs 2 mg/kg orally; for the rabbit the injected dose was 200 ~g/kg vs 10 mg/kg orally. The time course of the pressor response coincides with strong posi- tive inotropic effects (7,14). This is consistent with both effects being partly mediated through release of endogenous catecholamines (10,15,18). The injected monensin cleared from dog plasma too rapidly for loss due to metabolic transformation or elimination mechanisms. This is borne out by the rabbit studies in which the injected monensin was actually assayed for and appeared in tissues. We have also detected appreciable quantities of monensin in tissues of orally dosed chickens (3). The inference that monensin remains in the tissues after i t clears the blood is supported by the persistance of cardiovascular effects observed.

Differences in organ distribution of injected vs ingested monen~in in the rabbit are best accounted for by the ionophore being absorbed over a short time frame (injected, sacrificed within ten min) in those organs most extensively perfused by blood (heart, lung, kidney, brain, Table I I ) . Longer term oral ingestion experiments presumably reflect inherent tissue aff init ies, highest for l iver, kidney, brain, heart, and low for fat and muscle (Table I I I ) . This distribution suggests that ionophores seek out cell elements of intermediate polarity, neither protein nor neutral l ipid. A candidate for such a tissue component would be the phospholipid fraction which should be larger in metabolically active organs.

Rabbit plasma clears injected monensin appreciably more slowly (t½ ca. 8 min) than dog plasma (t½ ca. 2.5 min). Plasma clearance of orally ingested monensin also reflects species differences; rabbit plasma continues to rise 17 hr after monensin ingestion while dog plasma peaks at 90 min. These differences may reflect general differences between carnivores and herbivores.


I t has been reported that most of the monensin consumed in feed by chickens and steers is excreted in feces wi th in a day and 24 hr purged animals do not show a detectable amount of monensin in any t issue (1 ,2 ,5 ,6 ,8) . Keeping in mind that monensin is highly soluble in l i p ids (9) and that most of the in jected monensin clears rapid ly from the blood one might expect that animals fed monensin-supplemented feed for several days should have appreciable t issue levels of monensin.

We noted behavior ind icat ive of d istress in both conscious dogs and rab- b i ts receiving monensin. One hour a f te r being fed monensin (2 mg/kg) the dogs displayed rapid breathing, restlessness and i n a b i l i t y to support themselves on the i r limbs. The fed rabbits (I0 mg/kg) showed s imi lar behavior four to f i ve hr a f te r ingesting the ionophore. Rabbits also showed s imi lar tox ic manifesta- t ions one min a f te r in jec t ion (200 ~g/kg). In th is regard i t is in terest ing to note that the F.D.A. l i s t s the monensin LDofor dogs as between 10-20 mg/kg and the no e f fec t chronic level in feed as 200 ppm (19) which corresponds to ca. 4 mg/kg for a meal of 2% of body weight. Clear ly, our observations con- t rad i c t these claims.

I t is also of in te res t that t issue levels we found in rabbits fed a single bolus of monensin are in the neighborhood of 0.5 ~g/g, i . e . 0.5 ppm. In view of the fact that the maximal permitted residue of monensin in t issues of ca t t le and chicken set by the F.D.A. is 0.05 ppm this indicates that such a level is very easi ly achieved and exceeded in even casual non-chronic feeding experiments. Preliminary studies with chickens fed i i 0 ppm monensin for one week, as is the prevai l ing pract ice, great ly exceed the permitted t issue levels (3). Preliminary resul ts show that pigs, sheep and cats a l l show cardiovascular re- sponses to monensin s imi lar to those reported here for the dog and rabbi t .

We conclude that monensin has extremely potent cardiovascular ef fects on a wide var ie ty of animal species which are comparable whether the ionophore is administered intravenously or o ra l l y and which can cause behavioral d is t ress. Due to i t s favorable l i p i d s o l u b i l i t y i t easi ly passes through the gut into the blood and u l t imate ly into the t issues. In view of i t s widespread use as an animal feed supplement for meat producing animals, the impact on man of continuing exposure to monensin in the food supply requires careful re-eval- uation.

Acknowledgements

We thank Georgina del Valle for her technical assistance and Barbara Bradie and Lori Link for typing the manuscript. This work was supported by NIH grant HL 23932.

References

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Documents

Cardiovascular effects and pharmacokinetics of the carboxylic ionophore monensin in dogs and rabbits