EUROPEAN JOURNAL OF DRUG METABOLISM AND PHARMACOKINETICS, 1996, Vol. 21, No.3, pp. 223-226

Effect of Tamarindus indica L. on the bioavailability ofaspirin in healthy human volunteers

A. MUSTAPHAI, LA. YAKASAII and L ABDU AGUYE2

Departments of IPharmaceutical and Medicinal Chemistry and 2Pharmacology and Clinical Pharmacy, Ahmadu BelloUniversity, Zaria

Received for publication: February 6, 1995

Keywords: Tamarindus indica L., bioavailability of aspirin, human

SUMMARY

The influence of Tamarindus indica L. fruit extract incorporated in a traditional meal on the bioavailability of aspirin tablets 600 mgdose was studied in 6 healthy volunteers. There was a statistically significant increase in the plasma levels of aspirin and salicylic acid...respectively, when the meal containing Tamarindus indica fruit extract was administered with the aspirin tablets than when takenunder fasting state or with the meal without the fruit extract. The Cmax, AUC0-6h and tl/2 for aspirin increased from 10.04± 0.1 mg/mlto 28.62 ±0.21 mg/ml (P < 0.05); 14.03 ± 0.11 mg/ml.h to 86.51 ± 0.21 mg/ml.h (P< 0.085) and 1.04 ± 0.12 h to 1.50 ± 0.44 h (P <0.05) respectively. There was no change in the tmax (0.50 ± 0.17 h) but there was a decrease in the kel from 0.633 ± 0.22 to 0.463 ±0.29 (P < 0.05). Similarly, the Cmax , AUC0-6h and kel for salicylic acid rose from 43.84 ± 0.2 1 mg/ml to 68.19 ± 0.71 mg/ml (P <0.05); 171.59 ± 0.07 mg/ml.h to 266.22 ± 0.21 mg/mll.h (P < 0.05) and 7.37 ± 0.29 to 19.30 ±0.21 (P < 0.05), respectively. The tmax

decreased from 2.0 ± 0.18 h to 1.0 ± 0.08 h (P < 0.05) and tl/2 from 0.25 ± 0.21 h to 0.184 ± 0.11 h (P < 0.05). The study hasindicated that Tamarindus indicaL. fruit extract significantly increased the bioavailabilityof aspirin.

INTRODUCTION

Considerable interest has been shown in the possibleeffect of concurrent administration of traditional plantfood drug materials with conventional pharmaceuticalproducts. In developing countries, plant materials con­stitute the greater part of the dietary intake of the com­munity. The plants are either consumed raw or pre­pared in a special way as soup or stew to form part ofthe daily meal. In addition to this, plant materials may

Please send reprint requests to : Dr A. Mustapha,Department of Pharmaceutical and Medicinal Chemistry,Ahmadu Bello University, Zaria

be prepared in a form of traditional medicine for thetreatment or cure of a wide variety of ailments anddisease conditions.

It is an established practice that these plant-fooddrug materials are co-administered with conventionalmodern pharmaceutical products indirectly as part ofthe normal meal or: directly as medicinal preparation.Many of these plants contain pharmaco-active consti­tuents which may likely give rise to chemical or phar­maco-dynamic interactions with the conventionalpharmaceutical products. The importance of this inter­action to therapy is quite obvious. For example, theleafy part of many Hausa medicinal-food plants suchas Abrus precatorins, Hibiscus sabdoriffa and Momor­dica charantia are rich sources of calcium. Co-admin-

224 Eur. J. Drug Metab. Pharmacokinet., 1996, No.3

istration of these plant preparations in the form of con­ventional meal or medicinal preparations with tetracy­clines would indeed have adverse clinical effects (1­3). Similarly, reduced clinical efficacy of penicillinshas been reported following co-administration withfruits of Adansonia digitate, Psidium guajava and Ta­marindus indica (4).

The purpose of the present study was to evaluatethe effect of the fruit extract of Tamarindus indica L.on the bioavailability of acetylsalicylic acid. The fruitcould be taken alone or mixed with other ingredients,like lime-juice or honey, as a laxative and as a colddrink for patients with fever and dysentery. Of particu­lar interest is its common use among the Hausas in thepreparation of a pulp from cereals served as part ofbreakfast or given to the sick to stimulate appetite. Itsco-administration with acetylsalicylic acid and otherpharmaceutical products is a common practice amongthe local people.

MATERIALS AND METHODS

Materials

All chemicals used, unless otherwise stated, were ofanalytical grade. T. indica fruits were purchased fromthe local market. Aspirin was purchased from a phar­maceutical chemist's shop, while standard aspirin andsalicylic acid powders were from M & B LaboratoryChemicals Ltd. An SP8-100 UV spectrophotometer(Pye Unicam Ltd) and tablet dissolution and disinte­gration apparatus (Erweka) were employed in thestudy.

Methods

Identification tests, disintegration and dissolution ratetests and assay for content of active ingredient in theaspirin tablets were carried out as per the BP 1988procedure.

Preparation ofstandard meal (millet porridge)

About 50 g of finely powdered millet grain (Penninse­tum spp.) was placed in a clean I I bowl and about 40ml of water was added. The mixture was stirred with aspoon to produce a homogenous suspension. Boiledwater (500 ml) was added and stirred gradually to pro­duce a relatively light porridge which was furtherthickened by placing the bowl on a hot plate with con­stant stirring. The bowl was removed from the hot

plate and allowed to cool. The pH of the mixture was5.3.

T. indica water extract

Pieces of dried T. indica weighing about 60 g wereplaced in a clean I I conical flask and about 500 ml ofboiled water was added and allowed to soak for I h.The cooled water extract was filtered through a do­mestic sieve (100 mesh). The extract had a strong sourtaste.

Millet porridge with T. indica extract

The same procedure for the preparation of the milletporridge was followed as described earlier. While theporridge was still hot, 100 ml of the T. indica extractwas gradually added with stirring to produce a ho­mogenous mixture. The porridge was further thickenedby placing the bowl on the hot plate for about 10minutes with constant stirring. The final pH of themixture was 3.2.

In vivo study

Six healthy male volunteers participated in the study.The average age and weight of the volunteers were22.3 years and 61.3 kg, respectively. The volunteerswere clinically certified fit for the study and wereasked to refrain from taking any drug for at least 2weeks before the commencement of the study. Theywere all non-smokers and did not take alcohol. Awash out period of 2 weeks between trials wasadopted.

The first stage of the study involved the ingestionof a 600 mg dose of aspirin tablets with about 100 mlwater after overnight fasting. Food was withheld foranother 2 h after ingestion. Blood samples (5 ml) wereimmediately withdrawn prior to ingestion at 0.5, I, 2,3, 4, 5 and 6 h intervals via an indwelling cannula.The blood samples were placed in heparinized bottles,centrifuged for about 15 min at 2000 g and the plasmastored at -20°C pending analysis. The second stage in­volved the ingestion of a 600 mg dose of the aspirintablets with 100 ml water followed by the ingestion ofabout 200 ml of the prepared millet porridge withoutthe T. indica extract. Blood samples were similarlytaken and treated as in the first case. The third stageinvolved the ingestion of the 600 mg dose of aspirintablets with 100 ml water and the prepared millet por­ridge (200 ml) with T. indica extract. Blood sampleswere similarly taken and treated as described.

A. Mustapha et al., Tamarindus indica L. on aspirin 225

Table I : Chemical assessment of acetylsalicylic acid andsalicylic acidstandards and content of acetylsalicylic/salicylic acidin aspirin tablets as per BP 1988 requirement.

Table II : Disintegration and dissolution ratesof aspirintablets as per BP 1988 requirement.

Sample

Aspirin powder

Salicylic acid powder

Product AProduct B

Content (%)

99.90

104.50100.30

99.45

Sample

Product A

Product B

Mean disintegration

rate (6 tablets)

(min)

2.92± 0.423.17±0.98

Mean(%) release

rate at 45 min

(5 tablets)

100.0 ± 0.22

84.4± 0.30

Analysis

Plasma samples (I ml) were placed in a 20 ml extrac­tion tube and 2 ml of 0.05 M HCI was added. 10 ml ofethylacetate was then added and the mixture shakenfor 15 min using a mechanical shaker and centrifugedfor 15 min at 3000 g. The supernatant (5 ml) wastransferred into a second extraction tube and evap­orated to dryness on a water bath maintained at 40 ±10°C under a gentle stream of nitrogen passingthrough the tube. The residue was reconstituted in 5ml methanol and the absorbance taken at 231 nm and276 nm, respectively, using 1 em silica cuvettes andan SP8-100 UV spectrophotometer.

Calibration curves for both standard salicylic acidand acetylsalicylic (1-30 ug/rnl) were prepared. re­spectively, in plasma using the same procedure as de­scribed earlier.

The initial concentration of both aspirin and sal­icylic acid in the plasma at the specified time intervalwas estimated using the simultaneous equation formultiple component mixtures.

RESULTS AND DISCUSSION

Assay for content of active ingredient, disintegrationand dissolution rate tests of the two products of aspirintablets examined showed conformity with the BP 1988requirements (see Tables I and II). Product A, basedon its disintegration and dissolution rates was chosenfor the study. Linear calibration curves for acetylsal­icylic acid (1-30 ug/ml and salicylic acid (5-30ug/ml) .with good correlation coefficients (0.9978 and0.998) were obtained.

The mean estimated plasma pharmacokinetic par­ameters under the various study conditions for bothacetylsalicylic acid and its metabolic product, salicylicacid, are shown in Tables III and IV, respectively.

From the mean plasma pharmacokinetic data for ace­tylsalicylic acid, tmax. Cmax, AUC0-6h, tl/2 and lcel ob­tained under fasting conditions (tmax 0.50 ± 0.17 h;Cmax 10.04 ± 0.11 ug/ml: AUC0-6h 14.03 ± 0.11ug/ml/h; tl/2 1.04 ± 0.12 h; and lcel 0.638 ± 0.20) andwhen co-administered with the millet porridge alone(tmax 0.50 ± 0.17 h; Cmax 9.48 ± 0.70 ug/ml; AUC0-6h13.18 ± 0.11 ug/ml/h; tl/2 1.03 ± 0.2 hand lcel 0.678 ±0.1) were comparable. This indicates that the milletporridge which mainly consists of 72% carbohydrate,8% protein and 13.6% water has no influence on thepharmacokinetics of acetylsalicylic acid. Similarly, theestimated pharmacokinetic parameters for salicylicacid were also comparable under the two conditions(see Table IV).

Higher plasma levels of aspirin were obtainedwhen the drug was co-administered with 200 ml ofmillet porridge containing T. indica fruit extract. Forinstance, the Cmax increased from 10.04 + 0.11 ug/mlunder fasting conditions to 28.62 ± 0.21 ug/ml (P <0.05), when co-administered with millet porridge con­taining T. indica fruit extract.

Similarly, the AUC0-6h increased from 14.05 ±0.11 ug/ml/h to 86.57 ± 0.12 flg/ml/h (P < 0.05) whilethe tl/2 increased from 1.04 ± 0.12 h to 1.50 ± 0.44 h(P < 0.05), respectively, under the stated conditions.There was a decrease in the lcel from 0.638 ± 0.22 to0.463 ±0.29 (P < 0.05) under the conditions stated.

The significant increase in the plasma levels of sal­icylic acid is consistent with the increase in plasmalevels of acetylsalicylic acid following co-administra­tion of aspirin tablets (600 mg dose) with the milletporridge containing T. indica fruit extract. For in­stance, the Cmax increased from 43.84 ± 0.21 flg/*inlunder fasting conditions to 68.19 ± 0.71 ug/ml (P <0.05) when the volunteers took millet porridge con­taining T. indica fruit extract. Similarly, the AUC0-6hincreased from 171.59 ± 0.07 ug/ml/h to 266.22 ±0.21 flg/mllh (P < 0.05) under the stated conditions.

226 Eur. J. Drug Metab. Pharmacokinet., 1996, No.3

Table III : Pharmacokinetic parameters of acetylsalicylic acid after a single oral dose (600 mg) of aspirin to 6 human volunteers underdifferent conditions.

Conditions

Fasting

With millet powder

With millet porridge

and T. indica fruit extract

tmax Cmax AUC0-6h tin

(h) (p.glml) (JlglmVh) (h)

0.50 ± 0.17 10.04 ± 0.11 14.03 ± 0.11 1.04 ± 0.12

0.50 ± 0.17 9.48 ± 0.70 13.18 ± 0.11 1.03 ±0.2

0.50 ± 0.08 28.62 ± 0.21 86.51 ± 0.21 1.50 ± 0.44

P> 0.1 P< 0.05 P< 0.05 P < 0.05

Values are means ± SEM.

lcel

0.638 ± 0.22

0.678 ± 0.00

0.463 ± 0.29

P< 0.05

Table IV: Pharmacokinetic parameters of salicylic acid after a single oral dose (600 mg) of aspirin to 6 human volunteers underdifferent conditions.

Conditions

Fasting

With millet powder

With millet porridge

and T. indica fruit extract

tmax Cmax AUC0-6h iia

(h) (Jlglml) (JlglmVh) (h)

2.0 ± 0.18 43.84 ± 0.21 171.59 ± 0.07 0.28 ± 0.21

2.0 ±0.43 44.46 ± 0.29 158.29 ± 0.12 0.371 ±0.06

1.0 ± 0.08 68.19 ± 0.71 266.22 ± 0.21 0.184 ± 0.11

P< 0.05 P < 0.05 P < 0.05 P< 0.05

Values are means ± SEM.

7.37 ± 0.29

12.71 ± 0.44

19.30 ± 0.21

P< 0.05

Salicylate absorption occurs by passive diffusionprimarily of the unionised lipid-soluble moleculesacross the gastrointestinal (GIT) membranes (about60% absorbed from the stomach) and hence is in­fluenced by gastric pH. The millet porridge prepara­tion had a pH of 3.41 and it would be expected thatthis would bring about alteration of the GIT physio­logical pH in favour of more of the acetylsalicylic acidmolecules to be in the non-ionised lipid-soluble stateand hence more would be absorbed across the GITmembranes as indicated by the observed high plasmalevels. The fruit juice of T. indica contains free or­ganic acids, such as tartaric (10% pKa 2.93), citric andmalic acids and their salts, a little nicotinic acid andabout 30-40% invert sugar.

The present study has indicated that concomitantadministration of aspirin with millet porridge contain­ing T. indica' fruit extract will lead to a modificationof the physiological pH of the GIT in favour of anincrease in the absorption of the unionised lipid-so­luble molecules of the drug by passive diffusion across

the GIT membranes. The attending increase in theplasma level concentration of aspirin will indeed haveserious clinical implications, especially in patients tak­ing higher doses (4-6 g/day). It is obvious from thestudy that there is the need for careful evaluation ofthe possible interaction between food-plant prepara­tions with conventional pharmaceutical products espe­cially at this point in time when there is an increase inthe use of herbal medicine preparations world-wide inconjunction with synthetic pharmaco-active molecules.

REFERENCES

I. D'Arcy P.F., Mcelnay I.C. (1985) : Drug interaction in the gutinvolvingmetal ions. Drug Interact., 5, 83-112.

2. Duke lA. (I985) : Handbook of Medical Herbs. Boco Raton,CRC Press.

3. Welling P.G. (1977) : Influence offood and diets onabsorptionof drugs. J. Pharmacokinet. Biopharrn.,5, 29I

4. Watt I.M., Breyer-BrandwijkM.G. (I%2) : The Medical andPoisonous Plants of Southern and Eastern Africa, 2nd edn.London,Livingstone.