,University of Tanta ,Faculty of Pharmacy .

Department of Pharmaceutical Technology

Protocol of Study
For the partial fulfillment of the requirements of the Doctoral degree in Pharmaceutical Sciences (Biopharmaceutics) for Soha Mahmoud Ahmed El Masry / TITLE: Studies on Pharmacokinetics Interactions ggg Antihypertensive Drugs and Sildenafil Citrate. .

SUPERVISORS: Prof. Dr. Sanaa El-Gezawy Professor and head of Pharmaceutical Technology Departement Faculty of Pharmacy, University of Tanta . / Dr. Gamal El Magraby Assistant Professor of Pharmaceutical Technology Faculty of Pharmacy, University of Tanta /

:Introduction
Erectile dysfunction (ED) has a high prevalence among hypertensive men; the prevalence increases from 30% at the age of 50 years to 50% or more in patients aged over 70 years, i.e. 2-fold higher than that observed in normotensive subjects of the same age (Barbara et al., 2006). The available studies have not clarified the factor playing a major role in the pathogenesis of sexual dysfunction in hypertensive men. Neurovascular factors, however, seem to be especially important, (in particular defective nitric oxide activity), although hormonal and psychogenic factors cannot be excluded (Fogari and Zoppi, 2002). The incidence of sexual dysfunction is exacerbated by antihypertensive drug treatment (Fogari and Zoppi, 2002). These drugs that used to treat hypertension may cause ED. There is evidence that some classes of drugs, such as diuretics, centrally acting sympatholitic drugs, and -blockers have a greater impact on sexual function than other classes, such as calcium antagonists and angiotensin converting enzyme inhibitors. However, there is little trial-based evidence to indicate which drugs are more likely to cause this side effect. In general, thiazide diuretics and betablockers seem to cause ED more often (Mikhailidis et al., 2000). This suggests the higher chance for administration of therapeutic agents of E.D. in hypertensive patients. Accordingly there will be greater chance for drug - drug interaction between the antihypertensive drugs and any agent used to treat the E.D. due to concurrent administration. Sildenafil citrate (Viagra) is one of the most commonly used agent for management of ED (McMurray et al., 2007). It is one of phosphodiesterase-5 (PDE5) inhibitors was patented in 1996, approved for use in erectile dysfunction by the Food and Drug Administration on March 27, 1998. In rabbits, Sildenafil is rapidly absorbed after oral

administration, with absolute bioavailability of about 44%. It is eliminated predominantly by hepatic metabolism (mainly cytochrome P450 3A4) and is converted to an active metabolite with properties similar to the parent, sildenafil (Muirhead et al., 2002). Both sildenafil and the metabolite have terminal half lives of about 1.8 hours; its mean steady state volume of distribution (Vss) is 1-2 L/kg, indicating distribution into the tissues. Sildenafil and its major circulating Ndesmethyl metabolite are both approximately 90-92% bound to plasma proteins (Nichols et al., 2002; Walker et al., 1999). Thus the pharmacokinetics properties of sildenafil particularly its presystemic disposition and high plasma protein binding provide greater chance of interaction with many drugs that will be administrated concurrently. This effect will include the antihypertensive drugs. It was reported that sildenafil can be safely an effectively used in hypertensive patients receiving anti-hypertensive drugs (Albuquerque et al., 2005; Bhm et al., 2007). However this conclusion was reported without full pharmacokinetic study, accordingly there is a need to conduct a complete pharmacokinetic interaction between sildenafil and the commonly used antihypertensive drugs.

Objectives and Scope of the work:

The specific objective of this work will be to study the pharmacokinetics of sildenafil with selected antihypertensive drugs from - blockers and Angiotensin receptor blockers classes and this will be achieved by: 1. Development and validation of a sensitive and specific method for analysis of the sildenafil citrate and selected antihypertensive drugs in rabbit plasma.

2.

Calculation the pharmacokinetics parameters for both

sildenafil citrate and selected antihypertensive drugs in rabbit experimental rabbits plasma. 3. Studying the effect of sildenafil citrate on the pharmacokinetics and phrmacodynamic parameters of selected antihypertensive drugs and the effect of antihypertensive drugs on the pharmacokinetics parameters of sildenafil citrate when administrated with each other, i.e., the interaction between both drugs and their effect on each other in rabbits.

References:
Albuquerque, D., Miziara, L., Saraiva ,J.K., Rodrigues U. S., Ribeiro, A. B., and Wajngarten, M. " Efficacy, Safety and Tolerability of Sildenafil in Brazilian Hypertensive Patients on Multiple Antihypertensive Drugs. " Int Braz J Urol.; 31: 342-55, 2005. Barbara ,G., Chiara, L., Maria, G., Enrica, P., and Cardiovascular Prevention; 13 (1) : 7-11(5), 2006. Bhm, M., Burkart, M., and Baumann, G. "Sildenafil is well tolerated by erectile dysfunction patients taking antihypertensive medications, including those on multi drug regimens". Curr Drug Saf. ; 2(1):5-8, 2007. Fogari, R. , Preti, P. , Mugellini, A. , Derosa, G. , Marasi , G. , Corradi, L. , Zoppi, A. , Poletti, L. and Rinaldi, A. " P-10: Different effect of valsartan and lisinopril on sildenafil use in hypertensive men with erectile dysfunction. " Am J Hypertens; 15, 37A37A; doi: S08957061(02)02361-0, 2002. Alberto, M. "Hypertension and Erectile Dysfunction. " High Blood Pressure &

Fogari,R., and, Zoppi, A. "Effects of antihypertensive therapy on sexual activity in hypertensive men. " Current Hypertensive Reports; 4(3), 2002. Kloner, R. "Erectile dysfunction and hypertension. " International Journal of Impotence Research; 19: 296302, 2006. McMurray, J.G., Feldman, R.A., Auerbach, S.M., Deriesthal, H., Wilson, N.; and On behalf of the Multicenter Study Group "Longterm safety and effectiveness of sildenafil citrate in men with erectile dysfunction. " Ther Clin Risk Manag.; 3(6):975-981, 2007. Mikhailidis, D.P., Khan, M.A., Milionis, H.J., and Morgan, R.J. "The treatment of hypertension in patients with erectile dysfunction". Curr Med Res Opin.; 16 (1): 31-6, 2000. Muirhead, G. J., Rance, D.J., Walker, D. K. & Wastall, P. "Comparative human pharmacokinetics and metabolism of single-dose oral and intravenous sildenafil." British Journal of Clinical Pharmacology; 53 (s1): 13S-20S, (2002). Nichols, D.J., Muirhead, G.J.,and Harness, J.A. "Pharmacokinetics of sildenafil after single oral doses in healthy male subjects." Br J Clin Pharmacol; 53(Suppl. 1): 512, (2002). Walker, D.K., Ackland, M.J., James, G.C., Muirhead, G.J., Rance, D.J., Wastall, P., and Wright, P.A. " Pharmacokinetics and metabolism of sildenafil in mouse, rat, rabbit, dog and man. " Xenobiotica.; 29(3):297-310, 1996.