BIOPHARMACEUTICS & DRUG DISPOSITION, VOL. 14, 785-788 (1993)

SHORT COMMUNICATION

COMPARATIVE BIOAVAILABILITY OF PROPRANOLOL FOLLOWING ORAL, INTRAVENOUS AND TRANSDERMAL

ADMINISTRATION IN RABBITS

RAJESH KRISHNA*f AND J. K. PANDIT'

*Faculty of Pharmaceutical Sciences, University of British Columbia, 2146 East Mall, Vancouver BC V6T 123, Canada; 'Department of Pharmaceutics, Institute of Technology,

Banaras Hindu University, Varanasi 221005, Uttar Pradesh, India

KEY WORDS Propranolol Transdermal Bioavailability

INTRODUCTION

Beta blockers including propranolol suffer from a high degree of hepatic first- pass metabolism.2 One of the convenient methods to circumvent this pressing problem is to administer the drug transdermally. Recent advances in transdermal research have shown that drug delivery from this route has the advantage and convenience of rate controlled drug therapy. We have, in an earlier study, successfully developed a hydroxy propyl methyl cellulose based transdermal device. This study compares the bioavailability following oral and transdermal delivery of propranolol with reference to an intravenous bolus dose in rabbits.

MATERIALS AND METHODS

Materials

patch (6 mg). 1,4

Propranolol hydrochloride (Cipla Ltd, Bombay, India). Transdermal H-1

Experimental procedure

In vivo studies are based on a randomized cross over design. Six healthy male albino rabbits (Zoological Emporium, Varanasi, India) were selected (1 -2 + O - 3 kg)

$Address for correspondence.

01 42-2182/93/090185 -O4$01 .OO 0 1993 by John Wiley & Sons, Ltd.

Received 13 July 1993

786 R. KRISHNA AND J. K. PANDIT

0 1 2 3 4 Tirne(Hours)

Figure 1 . Concentration-time profile of propranolol administered intravenously in rabbits

100

90

60 > z 0 40

I ~ I 30

2 0

4

c z

z V 0 10 7-0--------

0 1 2 3 TIME (HOURS)

Figure 2. Concentration-time profile of propranolol administered orally in rabbits

___

35

30 ;:I 25 [O-\

10

5 0 04

0 5 10 15 20 25 30 35 40 45 50

TIME (HOURS)

Figure 3. Concentration-time profile of propranolol administered transdermally in rabbits

BIOAVAILABILITY OF PROPRANOLOL 787

and divided randomly into two groups. Each rabbit was fasted 24 h before dosing. Blood samples were removed from the central ear artery. A 5 d washout period was used in between treatments. Each rabbit received an i.v. bolus dose of propranolol in 0.9% w./v. sodium chloride into the marginal ear vein at the rate of 0.528 mg in 1 - 2 ml over 5 s (Figure 1). Arterial blood samples were withdrawn periodically and drug content determined in a LS-5 Perkin Elmer Spectrofluorimeter.' The 10.8 mg oral dose was administered as a solution in distilled water (10 ml) through a gastric tube (Figure 2). Transdermal discs, each containing 6 mg of drug, were attached to the inner pinna of the rabbit (Figure 3) and the dose administered was determined with respect to a blank patch and extracting the test patch after study.

Data analysis

Plasma propranolol levels following i.v. bolus administration were fitted using JANA and PCNONLIN. AUC, AUMC, mean residence time, biological half- life and dose normalized bioavailability were calculated using standard equations.5

RESULTS AND DISCUSSION

Figure 4 summarizes the results of the three routes of administration. Tables 1 and 2 are the data for the two-compartmental fit following i.v. administration and the comparative analysis of the three routes of administration. The extensive first-pass metabolism of oral propranolol is reflected in the relatively low bioavailability value of 3 3%. The highly vascularized area of the rabbit pinna, shown to be an excellent model for transdermal ~ tud ie s ,~ enables the transdermal permeation of propranolol to gain the advantages of i.v. bolus

80

70 t

m

0 m 30

10

0 -

1 _1_

2

8

ORAL INTRAVENOUS H - l TDOS

Figure 4 . Comparative bioavailability following three different routes of administration in rabbits

788 R. KRISHNA AND J. K . PANDIT

Table 1 . Two-compartmental fit following in vivo administration of propranolol in rabbits

Parameter Value

95.585 18-781 2.019 0.121 47 1.224 0.343 5.706 0.566 1 * 141 0.433

Table 2. Comparative analysis of three routes of propranolol administration

Parameter I. v. bolus Oral Transdermal

Dose (mg) P (h-9 t,B (h) AUC,.., (ng h ml-I) AUMC,-, (ng h2 ml-I) MRT (h) Bioavailability (Yo)

0.528 0.1215

5.7 184.28

1142.35 6 - 198

100

10.8 1 a386 0-5

125.47 201.35 1-605 3-329

2-78 0.126

5.5 625.664

1 1 542.51 18-45 64.48

therapy. In addition, a sustained effect is also noted by the prolonged mean residence time of the drug in the body.

CONCLUSION

The transdermal H- 1 patch enhanced the bioavailability by 20-fold compared to the oral route and a prolonged mean residence time was observed. Effective plasma concentrations of 15-20 ng ml- in rabbits were maintained for about 15 h.

REFERENCES

1. R. Krishna, Development and evaluation of transdermal drug delivery systems of a model P-

2. J. G. Riddell, D. W. G. Haron and R. G. Shanks, Clinical pharmacokinetics of P-adrenoreceptor

3. M. Corbo, J. C. Liu and Y . W. Chien, Transdermal controlled delivery of propranolol from

4. R. Krishna and J. K. Pandit, unpublished data. 5. M. Gibaldi and D. Perrier, Phurmucokinetics, Vol. 15, Marcel Dekker, New York, 1982.

blocker. M.Pharm. Thesis, Banaras Hindu University, Varanasi, India, 1992.

antagonists. An update. Clin. Phurmucokinet., 12, 305-320 (1987).

a multi-laminate adhesive device. Pharm. Res., 6 , 753 (1989).