Mechanism of enhanced drug effects produced by dilution of the oral dose

Mechanism of enhanced drug effects produced by dilution of the oral dose

~OXICOLOGYANDAPPLIED PHARMACOLOGY 19,164168(1971) Mechanism of Enhanced Drug Effects Produced by Dilution of the Oral Dose1 J.-L. BOROWITZ, P. F. M...

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~OXICOLOGYANDAPPLIED

PHARMACOLOGY

19,164168(1971)

Mechanism of Enhanced Drug Effects Produced by Dilution of the Oral Dose1 J.-L. BOROWITZ, P. F. MOORE,~ G. K. W.

YIM,

AND

T. S. MIYA

Department of Pharmacology and Toxicology, College of Pharmacy and Pharmacal Sciences, Purdue University, Lafayette, Indiana 47907 Received July 23, 1970

Mechanismof EnhancedDrug Effects Producedby Dilution of the Oral Dose.BOROWITZ, J. L., MOORE, P. F., YIM, G. K. W., andMIYA, T. S.(1971). ToxicoI. Appl. Pharmacol. 19,164168. Drugs which areweakacidsor weak basesand drugs with limited water solubility are more toxic by the oral route when given in dilute solution or suspension.The onsetof sleepafter po administrationof sodiumpentobarbital(50 mg/kg) isfasterin rats when the drug isgiven in dilute solution (5 ml/100g body wt) than whenit isgiven in concentratedsolution (0.5 ml/100 g body wt). However, administration of water po (5 ml/100 g body wt) doesnot affect the ip toxicity of aminopyrine. Sodium salicylateplasmalevelsare significantly higher in rats after the drug is given po in dilute (0.8 %) solution than when it is given po in concentrated (25%) solution. Thesedata indicatethat drugsareabsorbedmorerapidly into the systemic circulation whengiven po in dilute rather than concentratedsolution. Two mechanismsappearto be involved in the increasedtoxicity phenomenon with low concentrations of drugs: (1) rapid stomachemptying and (2) exposureto a large absorptivesurfaceof drug solutionsgiven po in a relatively large fluid volume. Drugs are known to be more toxic when administered po in dilute rather than in concentrated aqueoussolution (Borowitz et al., 1957; Moore et al., 1960; Ferguson, 1962). It has been suggested(Ferguson, 1962)that the volume of fluid alters not only toxicity but also many other pharmacologic responsesand determinations. The present study examinesthe possibility that dilution of drug solutions given orally results in more rapid absorption of drugs into the systemic circulation. METHODS Adult albino rats3of either sex(weighing approximately 300g) were usedin this study. In each experiment, groups of animals were matched according to weight and sex distribution. The animals were fasted 20-30 hr before treatment. The po doseswere administered by stomach tube. In the acute toxicity studies, the number of deaths 1Work supportedin part by PurdueDavid Ross Fellowshipand NIH Grant, GM 15005. * Presentaddress:CharlesPfizer Company,Groton, Connecticut. 3HarlanAnimal Industries,Cumberland,Indiana. 164

ENHANCED

EFFECT

BY DILUTION

OF ORAL

165

DOSE

recorded were those which occurred within 24 hr after dosing. No ill effects were noted from the amounts of water administered orally to the rats used in this study. To estimate salicylate in plasma, the method of Keller (1947) as modified by Cosmides et al. (1956) was used. To obtain the plasma samples,the rats were decapitated after exposure to chloroform vapors. After decapitation, 6 ml of blood was collected in a vesselwetted with concentrated sodium oxalate solution and centrifuged for 15 min. The supernatant was used for determination of salicylate.

RESULTS Efect

of Concentration

on the Toxicity

of Drugs

Given Orally

Table 1 showsthat the toxicities of a weak acid, a weak base,and a compound with limited water solubility are all similarly affected by dilution of the oral dose. After administration of the dilute dose of aminopyrine or sodium salicylate, death usually occurred within a few minutes. Therefore, any mechanismproposed to explain the phenomenon of enhanced drug action due to dilution of the oral dose must account for the rapid onset of effect. TABLE EFFECT

OF CONCENTRATION

ON THE TOXICITY

~Atropine sulfate (130) Aminopyrine (1000) Sodiumsalicylate(1600)

OF DRUGS

919 lSjl5 s/10

;bs 1.6

a All differences in toxicity between 2 y0 level by the chi square test. b Suspended in 2 o/o sodium alginate.

Eflect of Dose Dilution

IN RATS

Dilute solution ~~~~ Cont. No. deaths/ No. animals ( %)

Drug and dose (mg/W

the

1

the

on Barbiturate

dilute

and

concentrated

GIVEN

ORALLY”

Concentratedsolution Cont. (“4,

No. deaths/ No. animals

30 lob

O/9 7120 l/l0

64 solutions

are

significant

at least

at

Sleep Time

Two groups of 10 rats each were given 50 mg!kg of pentobarbital sodium by stomach tube. One group received a 0.1% solution of the drug whereasthe other group received a 1.Oy0 solution. The average time of onset of sleepin the group treated with the dilute dose was 4.9 min, and after administration of the concentrated dose, the average time of onset of sleepwas 7.1 min. The difference is significant at the 1y0 level. Thus, in the caseof pentobarbital sodium, dilution of the oral doseenhancesthe onsetof the pharmacologic effect as well as the toxicity as noted by Borowitz et al. (1957) and Ferguson (1962). Eflect

of Oral

Water on Intraperitoneal

Toxicity

of Aminopyrine

If cellular hydration or altered drug distribution were involved in the enhanced responsefrom the dilution of the dose, changing the route of administration of the drug should not modify the enhancedresponse.Accordingly, 200 mg/kg of aminopyrine was

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ET AL.

given ip to 2 groups of 11 rats each. One group received in addition 50 ml/kg of water po. Three rats died in the group receiving water; 4 in the nonwater-treated group. Thus, oral water treatment appears to have no influence on the toxicity of ip administered aminopyrine. It therefore seems unlikely that the excess water alters either drug receptor interactions or drug distribution.

Efect of Dilution of the Dose on Salicylate Blood Levels If dose dilution enhances drug absorption from the gastrointestinal tract, higher blood levels of drug should be seen in animals treated po with dilute doses. A nonfatal dose of sodium salicylate, 400 mg/kg, was administered po to rats in dilute (0.8 %) and concentrated (25 %) aqueous solution. Plasma salicylate was determined 10, 30,60, and

L-~--l 100 Minutes

120

AfterAdmlnlstratlon

FIG. 1. Plasma salicylate levels after oral administration of dilute and concentrated solutions of sodium salicylate (400 mg/kg) to rats. Each point is a mean of 10 determinations.

120 min after dosing. The data in Fig. 1 show that salicylate blood levels are significantly higher in animals treated with the diluted doseat 10 and 60 min after po administration (p < 0.01 at both 10 and 60 min). These results suggest that absorption of sodium salicylate is enhanced when a relatively large amount of water is administered with the dose of the drug.

Eflect of Volume on Stomach Emptying The large volumes of water (up to 5 % of body weight) given po in the above experiments may have induced a rapid emptying of the stomach resulting in enhanced absorption. To test this possibility, rats were given a dye solution (brilliant blue) in either a large (5 % of the body weight) or small (0.5 % of the body weight) volume by stomach tube. The distance the dye solutions traveled down the intestinal tract was measured at time intervals after dosing. When the animals were examined as soon as possibleafter administration of the large volume, the dye had traversed 78 to 93 % of the length of the small intestine. By contrast, at the sametime interval after administration, only 7 to 9 % of the length of the small intestine had beenreached by the dye injected in

ENHANCED

EFFECT

BY DILUTION

OF ORAL

DOSE

167

a small volume. When the animals were examined 2 min after dosing, the dye given in the large volume had traversed 90 to 100 % of the small intestine, whereas the dye given in the small volume had reached only 14 to 25 % of the small intestine. Even after 30 min, only 5 1 to 54 y/, of the length of the small intestine had been reached by the small volume of dye solution. Thus, when a drug is given in dilute solution, it has access to a greater surface area than when it is given in concentrated solution. DISCUSSION There are at least two possible explanations for the enhancement of drug effects produced by dilution of po doses. One, a more rapid stomach emptying and secondly, the exposure of the drug to a more extensive surface area resulting in more rapid absorption from the intestines. Fluid passes into the duodenum shortly after being drunk by the human subject, not continuously, but in spurts (Baird et al., 1924). It is evident from the present study in rats that a relatively large volume of fluid administered po quickly reaches a large portion of the gastrointestinal tract. Thus, dissolved or suspended drug given po with a relatively large volume of fluid would almost immediately have access to a large absorptive surface. Stomach emptying is thought to be retarded in proportion to the osmolarity of the solution introduced into the stomach. In dogs, emptying time was found to be correlated with the freezing point of the administered meal (McSwiney and Spurrell, 1933). Milk alone or with added glucose or sodium chloride delayed stomach emptying in proportion to the degree of freezing point depression produced by the added solutes. It was also found that hypotonic meals (dialyzed milk) leave the stomach more rapidly than isotonic meals. An action on the duodenum is thought to explain the delay in stomach emptying by glucose solutions of high osmolarity (Quigley and Phelps, 1934). By the same mechanism, drug solutions of relatively high osmolarity may leave the stomach slowly and may therefore have limited access to the large absorptive surface of the intestine. Simon (1935) investigated the influence of the osmolarity of the solution on intestinal absorption of potassium iodide and strychnine in rabbits. Tonicity was regulated by addition of sodium chloride to the solution of the drug, and the dose of the drug per unit body weight was held constant. The dose volume was also constant per unit body weight. Since the solutions were introduced directly into ligated intestinal sections, emptying time of the stomach was of no consequence. After introducing a potassium iodide solution (40 ml/kg of body weight, 0.05 g/100 ml solution) into a ligated intestinal section, iodide ion was detected in the blood in 2 min. When sodium chloride (0.9 or 2.75 mg/lOO ml) was also included in the potassium iodide solution, no iodide ion could be detected in the blood 12 min after administration. Strychnine exerted its convulsive action most quickly after administration of a hypotonic dose into ligated rabbit intestinal sections, less quickly after an isotonic dose and most slowly after a hypertonic dose. Slow absorption of hypertonic drug solutions from the intestines may also help to explain the lesser toxicity of more concentrated drug doses found in the present study. Preliminary results indicate that d-tubocurarine (intocostrin) given po in dilute aqueous solution (15 mg/kg with 50 ml/kg of water) to rats does not produce any gross

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ET

AL.

pharmacologic effects. Thus, drug types which are not usually absorbed po are not better absorbed on dilution of the po dose. Apparently, the normal integrity of the gastrointestinal mucosa is not qualitatively changed by po administration of dilute drug solutions. Goodman and Gilman (1970) stated that concentrated drug solutions given po are more rapidly absorbed than dilute solutions. In the studies reported here the opposite is true. These results have important implications in clinical medicine and toxicology as well as in experimental pharmacology. REFERENCES J. M. H., and HERN, J. R. B. (1924). The importance of estimating chlorides in the fractional test meal samples, and some experiments with the duodenal tube. Guy’s Hosp. Rep. 74, 23-54. BOROWITZ, J. L., YIM, G. K. W., MIYA, T. S., and CARR, C. J. (1957). Effect of concentration on oral toxicity of drugs. Fed. Proc., Fed. Amer. Sot. Exp. Biol. 16, 284, Abstract, COSMIDES, G. J., STEMLER, F. W., and MIYA, T. S. (1956). Calorimetric comparison of plasma salicylatelevelsfollowing the oral administrationof certain salicylatesto rabbits. J. Amer. Pharm. Ass. Sci. Ed. 45, 16-20. FERGUSON, H. C. (1962). Dilution of dose and acute oral toxicity. Toxicol. Appl. Pharmaco/. 4,759-762. GOODMAN, L. S., and GILMAN, A. (1970). The Pharmacological Basis of Therapeutics, 4th ed., BAIRD,

M.

MC.,

CAMPBELL,

p. 5. Macmillan, New York. W. J., JR. (1947).A rapid method for the determinationof salicylatesin serumor plasma.Amer. J. Clin. Pathol. 17, 415417. MCSWINEY, B. A., and SPURRELL, W. R. (1933).Influenceof osmoticpressureon the emptying KELLER,

time of the stomach. J. Physiol. (London) 79, 43742. P. F., YIM, G. K. W., and MIYA, T. S. (1960). Effect of concentration on oral toxicity of drugs. Fed. Proc., Fed. Amer. Sot. Exp. Biol. 19, 390, Abstract. QUIGLEY, J. P., and PHELPS, K. R. (1934). The mechanism of gastric motor inhibition from ingested carbohydrates. Amer. J. Physiol. 109, 133-138. SIMON, I. (1935). Della rapidita di assorbimento dei farmaci a secondu della pressione osmotica delle soluzioni in cui sono contenuti. Arch. Int. Pharmacodyn. 35, 180-194. MOORE,