**4. The renin-angiotensin system and its relationship with pathophisiology hypertension**

The pathophysiology of hypertension is defined as a lasting elevation of blood pressure to ≥ 140/90 mmHg, as this procedure was used because most individuals with this pressure range belong to risk group cardiovascular disease and hypertension arising from the medical attention they deserve. This disease is like the most common cardiovascular disease and its prevalence increases with age.

The RAS participates as a key player in regulating blood pressure in both long and short term. This happens because the increase, even in modest concentrations of angiotensin II leads to an acute elevation of blood pressure. To get an idea in terms of values to angiotensin II is about 40 times more potent than norepinephrine and effective concentration (EC50) to angiotensin II acute elevation of blood pressure is approximately 0.3 nmol / l. In the presence of angiotensin II administered intravenously pressure rises in a few seconds and after a few minutes this reduces the normal rate. This effect is known as immediate pressor response is due to a rapid increase in total peripheral resistance. This increased resistance is a response that maintains blood pressure in the presence of an acute hypotensive response. Although the direct effects of angiotensin II on cardiac contractility and heart rate indirect in the rapid rise in blood pressure leads to activation of the baroreceptor reflex, and in a negative feedback, this occurs with the reduction of sympathetic tone and increase vagal tone.

On the other hand, there is a slow pressor response, which also occurs by the action of angiotensin II. Response to this pressure is stabilized for a long time. This slow pressor response is most likely due to reduced renal excretion function, causing an increase in fluid retention and salt and, with increasing pressure quently. Associated with these renal effects, angiotensin II in this response also induces the synthesis of endothelin-1 and superoxide anion, which can contribute to this type of slow pressor response. Other classical effects of

is a strong relationship between the amount of circulating *angiotensinogen* in plasma and increased blood pressure, so the use of oral contraceptives containing estrogen lead to an increase in serum angiotensinogen, thereby resulting in an elevation of blood pressure. At this point becomes more clear also the strong relationship with the inflammatory process. We have seen that directly interferes with the prostaglandin release of renin, ie, prostaglandins increase the secretion of this hormone by binding to adenosine receptors.

**Angiotensin Converting Enzyme (ACE):** ACE is a glycoprotein ecto-enzyme and that in addition to cleaving angiotensin I to angiotensin II forming this ecto-enzyme can also inactivate bradykinin, because ACE is very nonspecific and can cleave dipeptide units with many amino acid substrate. Therefore, the ACE inhibitors such as captopril and lisinopril, for example, are able to increase bradykinin and reduce angiotensin II. The rapid in vivo conversion of angiotensin I to II occurs through the action of ACE that is present on the luminal surface of endothelial cells throughout the vascular system. In addition to these effects of ACE some studies show the existence of a carboxypeptidase-related enzyme called ACE2 is capable of cleaving angiotensin I into (angiotensin 1-9) and angiotensin II (angiotensin 1-7). This enzyme is not inhibited by classic ACE inhibitors. Its physiological

**4. The renin-angiotensin system and its relationship with pathophisiology** 

The pathophysiology of hypertension is defined as a lasting elevation of blood pressure to ≥ 140/90 mmHg, as this procedure was used because most individuals with this pressure range belong to risk group cardiovascular disease and hypertension arising from the medical attention they deserve. This disease is like the most common cardiovascular disease

The RAS participates as a key player in regulating blood pressure in both long and short term. This happens because the increase, even in modest concentrations of angiotensin II leads to an acute elevation of blood pressure. To get an idea in terms of values to angiotensin II is about 40 times more potent than norepinephrine and effective concentration (EC50) to angiotensin II acute elevation of blood pressure is approximately 0.3 nmol / l. In the presence of angiotensin II administered intravenously pressure rises in a few seconds and after a few minutes this reduces the normal rate. This effect is known as immediate pressor response is due to a rapid increase in total peripheral resistance. This increased resistance is a response that maintains blood pressure in the presence of an acute hypotensive response. Although the direct effects of angiotensin II on cardiac contractility and heart rate indirect in the rapid rise in blood pressure leads to activation of the baroreceptor reflex, and in a negative feedback, this occurs with the reduction of

On the other hand, there is a slow pressor response, which also occurs by the action of angiotensin II. Response to this pressure is stabilized for a long time. This slow pressor response is most likely due to reduced renal excretion function, causing an increase in fluid retention and salt and, with increasing pressure quently. Associated with these renal effects, angiotensin II in this response also induces the synthesis of endothelin-1 and superoxide anion, which can contribute to this type of slow pressor response. Other classical effects of

importance is not yet clear.

and its prevalence increases with age.

sympathetic tone and increase vagal tone.

**hypertension** 

angiotensin II on the pathophysiology of hypertension is the morphological alteration of the cardiovascular system, causing hypertrophy of cardiac and vascular cells, and increase the synthesis and deposition of collagen by cardiac fibroblasts.

#### **5. Antihypertensive drugs and its relationship to inflammation**

As discussed previously classicaly, the rennin-angiotensin system (RAS) has been considered a hormonal circulating system. The so-called systemic or circulating RAS plays a crucial role in the maintenance of blood pressure and electrolyte as well as fuid homeostasis15. This is mediated through its constrictive actions on vascular smooth muscle and by its influence on aldosterone secretion from the adrenal cortex, electrolyte transport in kidney, and on thirst as well as sodium appetite in the brain. In addition to its actions on the cardiovascular, renal, and nervous system, the expression of local RAS components in tissues such as the brain, kidneys, adrenals and gonads has led to the proposition that these components may either potentate systemic functions, or have entirely separate activities meeting the specific needs of these individual tissues.There is accumulating evidence that changes in tissue/organ-specific RAS may be associated with the pathophysiology of the respective tissue/organ functions (Ip et al., 2003).

The final goal of the RAS is the angiotensin II production that acts through the interaction with two pharmacologically defined receptor subtypes, namely type 1 (At1) and type 2 (At2) that are distributed in numerous target tissues and organs like pancreas, for example (Chan et al., 2000).

Some studies show that AT1 and AT2 receptors when activated by angiotensin II may lead to tissue that expresses inflammatory responses develop. This is the case of acute pancreatitis, which expresses the receptor AT1a more significantly than the receiver AT1b. In contrast, the AT2 receptor is most often responsible for these inflammatory responses more pronounced.

The role of RAS in the inflammatory process was further evidenced by the ability of an ACE inhibitor to suppress inflammation and subsequent tissue injury (Pupilli et al., 1999). Some studies suggest that losartan, an At1 blocker, and lisinopril, an angiotensin-converting enzyme (ACE) inhibitor, can inhibit both the liver fibrosis and portal hypertension occurring in secondary biliary cirrhosis by inhibiting hepatic stellate cells (HSCs) activation (Agarwal et al.,1993). Other studies in vitro of cultured pancreatic stellate cells have demonstrated that these cells exhibit morphological and functional features similar to cultured hepatic stellate cells, including positive SMA staining after a period of time in culture, increased proliferation in response to PDGF, and increased collagen synthesis in response to TGF-β (Gressner et al., 1995). So these stellate cells could trigger an inflammatory process in the tissue which is expressed.

Although other tissues, these stellate cells can not express the AT1 and AT2 receptors are widely distributed throughout the system and this can lead to a local inflammatory response by angiotensin II signaling. Given this relationship, it is necessary to comment briefly on the mechanism of action of antihypertensive agents shown below.

**ACE Inhibitors:** The essential effect of the agents belonging to this group of drugs is just the inhibition of the conversion of angiotensin I to II. In this respect ACE inhibitors are selective

Hypertension and Renin-Angiotensin System 91

angiotensin II has several other effects not only of increased blood pressure. These effects range from increased expression of proto-oncogene to the inflammation process. In the last decade studies have shown a strong relationship that RAS blockers possess anti atherosclerosis not only by regulating blood pressure, but also for its anti-inflammatory and antioxidant (Montecucco et al, 2009 and Schmieder et al, 2007 ). In this sense it is observed that studies that angiotensin II also acts on the expression of adhesion molecules such as intracellular adhesion molecule (ICAM), vasocelular adhesion molecule (VCAM), the Pselectin molecules expressed in the inflammatory process, and promote the expression of chemokines, growth factors and cytokines. Our study showed that angiotensin promotes the activation of certain stellate cells, which promote active since the deposition of collagen formation and fibrosis. So regardless of the mechanisms involved ACE inhibitors have broad clinical utility as antihypertensive agents, but also has a great potential for the

Similarly antagonists of angiotensin II receptor act in lowering blood pressure, but unlike the effects of ACE inhibitors are not from inhibition of angiotensin II formation, but inhibition of its effects by antagonism of this peptide . This class of drugs bind to the AT1 receptor with high affinity and, in general, are around 10,000 times more selective for this receptor than for the AT2. The pharmacology of these antagonists is well described in the literature. Goldman and Gilman shows that studies in vitro and in vivo of these drugs block the majority of the biological effects of angiotensin II such as contraction of vascular smooth muscle, fast pressor responses, slow pressor responses, thirst, release of vasopressin, aldosterone secretion , release of catecholamines by the adrenal glands, increased noradrenergic neurotransmission, increased sympathetic tone, impaired renal function, cellular hypertrophy and hyperplasia, and inhibit the activation of pancreatic stellate cells, protecting from injuries such as acute pancreatitis, the latter effect was observed by Silva, RB. et al, 2010. Drugs that make up this group are: *candesartan, eprosartan, ibesartan, losartan,* 

Given this overview of the RAS and its relation to inflammation, we can observe that the drugs used to treat hypertension are consistent with the possible protective effects of a serial of inflammatory disorders. However the application of these to treat acute problems like apancreatite, for example, is not observed, but promising results from several studies, show that these drugs may be important in the treatment of various inflammatory disorders, is atherosclerosis, ischemia , or even pancreatitis. We observed in our work that pancreatic stellate cells respond to the action of angiotensin II (Figure 3 and 4) and in addition, we observed that these respond directly, because these cells have receptors for angiotensin II AT1 as illustrating the existence of even a Local RAS, regulating the vasculature of the tissue in question. Because of this, these drugs as mentioned above, could be a viable alternative to

In our study we observed that the strength pancreatic stellate cells in collagen production are involved during acute pancreatitis and possibly that these can become active cells through the action of angiotensin II produced by rennin-angiotensin system. However it has been suggested an increasingly close relationship between the RAS and the inflammatory process in this sense these studies indicate a relationship of therapy used to treat

hypertension is also feasible in other disorders such as inflammatory problems.

therapy of other vascular disorders, and it is observed in experimental models.

*olmesartan, telmisartan and valsartan.* 

treat these other disorders.

drugs, but because ACE has multiple substrates, these inhibitors may induce effects not related to reduced synthesis of angiotensin II. Among these various effects is the increased synthesis of bradykinin and prostaglandins that may contribute to the effects of ACE pharmacological inhibitors. A study by Silva, RB et al. (2010) in the Faculty of Medicine of Ribeirão Preto - FMRP / USP, Sao Paulo - Brazil, demonstrated that the application of drugs such as Lisinopril significantly reduced inflammatory response in an experimental model of acute pancreatitis, illustrating the relationship between the RAS and inflammation , figure 2.

Fig. 2. Map showing histopathological in (A) - The severe inflammatory process in the experimental group of acute pancreatitis and (B) - A significant reduction in inflammation in animals treated with lisinopril (Silva, R et al, 2010).

**Captopril:** Captopril was the first ACE inhibitor to be marketed. This drug has a bioavailability of about 75% and undergoes rapid absorption. Most of this drug is excreted in the urine, about 40 to 50% in the form of captopril and the remainder in the form of dimers. Captopril contains a sulfhydryl group.

**Enalapril:** enalapril is a pro-drug hydrolyzed by esterases in the liver. After this hydrolysis, enalapril is converted into a dicarboxylic acid which is known as enalaprilat a highly potent inhibitor of ACE.

**Lisinopril:** This drug differently than enalapril, it is active. In vitro studies show that Lisinopril is an ACE inhibitor slightly more potent than enalaprilat. Our study showed that this drug also has significant anti-inflammatory effects, but these results we have shown this relationship only in a specific experimental model of acute pancreatitis, requiring a slightly larger study, to ascertain whether this behavior also occurs in human beings. Lisinopril does not accumulate in the tissues.

**Fosinopril:** This drug contains a phosphinate group that binds to the active site of ACE. Liver esterase is cleaved and, with this prodrug that is converted to fosinopril, more potent than captopril and less potent than enalaprilat.

In pathological conditions such as hypertension, ACE inhibitors promote the reduction of systemic vascular resistance and various hypertensive states. This effect, as mentioned above arises from the action of reducing the production of angiotensin II, thereby reducing their pressor effects and vascular remodeling. But what must be understood is that

drugs, but because ACE has multiple substrates, these inhibitors may induce effects not related to reduced synthesis of angiotensin II. Among these various effects is the increased synthesis of bradykinin and prostaglandins that may contribute to the effects of ACE pharmacological inhibitors. A study by Silva, RB et al. (2010) in the Faculty of Medicine of Ribeirão Preto - FMRP / USP, Sao Paulo - Brazil, demonstrated that the application of drugs such as Lisinopril significantly reduced inflammatory response in an experimental model of acute pancreatitis, illustrating the relationship between the RAS and inflammation , figure 2.

A B

**Captopril:** Captopril was the first ACE inhibitor to be marketed. This drug has a bioavailability of about 75% and undergoes rapid absorption. Most of this drug is excreted in the urine, about 40 to 50% in the form of captopril and the remainder in the form of

**Enalapril:** enalapril is a pro-drug hydrolyzed by esterases in the liver. After this hydrolysis, enalapril is converted into a dicarboxylic acid which is known as enalaprilat a highly potent

**Lisinopril:** This drug differently than enalapril, it is active. In vitro studies show that Lisinopril is an ACE inhibitor slightly more potent than enalaprilat. Our study showed that this drug also has significant anti-inflammatory effects, but these results we have shown this relationship only in a specific experimental model of acute pancreatitis, requiring a slightly larger study, to ascertain whether this behavior also occurs in human beings. Lisinopril does

**Fosinopril:** This drug contains a phosphinate group that binds to the active site of ACE. Liver esterase is cleaved and, with this prodrug that is converted to fosinopril, more potent

In pathological conditions such as hypertension, ACE inhibitors promote the reduction of systemic vascular resistance and various hypertensive states. This effect, as mentioned above arises from the action of reducing the production of angiotensin II, thereby reducing their pressor effects and vascular remodeling. But what must be understood is that

Fig. 2. Map showing histopathological in (A) - The severe inflammatory process in the experimental group of acute pancreatitis and (B) - A significant reduction in inflammation in

animals treated with lisinopril (Silva, R et al, 2010).

dimers. Captopril contains a sulfhydryl group.

than captopril and less potent than enalaprilat.

inhibitor of ACE.

not accumulate in the tissues.

angiotensin II has several other effects not only of increased blood pressure. These effects range from increased expression of proto-oncogene to the inflammation process. In the last decade studies have shown a strong relationship that RAS blockers possess anti atherosclerosis not only by regulating blood pressure, but also for its anti-inflammatory and antioxidant (Montecucco et al, 2009 and Schmieder et al, 2007 ). In this sense it is observed that studies that angiotensin II also acts on the expression of adhesion molecules such as intracellular adhesion molecule (ICAM), vasocelular adhesion molecule (VCAM), the Pselectin molecules expressed in the inflammatory process, and promote the expression of chemokines, growth factors and cytokines. Our study showed that angiotensin promotes the activation of certain stellate cells, which promote active since the deposition of collagen formation and fibrosis. So regardless of the mechanisms involved ACE inhibitors have broad clinical utility as antihypertensive agents, but also has a great potential for the therapy of other vascular disorders, and it is observed in experimental models.

Similarly antagonists of angiotensin II receptor act in lowering blood pressure, but unlike the effects of ACE inhibitors are not from inhibition of angiotensin II formation, but inhibition of its effects by antagonism of this peptide . This class of drugs bind to the AT1 receptor with high affinity and, in general, are around 10,000 times more selective for this receptor than for the AT2. The pharmacology of these antagonists is well described in the literature. Goldman and Gilman shows that studies in vitro and in vivo of these drugs block the majority of the biological effects of angiotensin II such as contraction of vascular smooth muscle, fast pressor responses, slow pressor responses, thirst, release of vasopressin, aldosterone secretion , release of catecholamines by the adrenal glands, increased noradrenergic neurotransmission, increased sympathetic tone, impaired renal function, cellular hypertrophy and hyperplasia, and inhibit the activation of pancreatic stellate cells, protecting from injuries such as acute pancreatitis, the latter effect was observed by Silva, RB. et al, 2010. Drugs that make up this group are: *candesartan, eprosartan, ibesartan, losartan, olmesartan, telmisartan and valsartan.* 

Given this overview of the RAS and its relation to inflammation, we can observe that the drugs used to treat hypertension are consistent with the possible protective effects of a serial of inflammatory disorders. However the application of these to treat acute problems like apancreatite, for example, is not observed, but promising results from several studies, show that these drugs may be important in the treatment of various inflammatory disorders, is atherosclerosis, ischemia , or even pancreatitis. We observed in our work that pancreatic stellate cells respond to the action of angiotensin II (Figure 3 and 4) and in addition, we observed that these respond directly, because these cells have receptors for angiotensin II AT1 as illustrating the existence of even a Local RAS, regulating the vasculature of the tissue in question. Because of this, these drugs as mentioned above, could be a viable alternative to treat these other disorders.

In our study we observed that the strength pancreatic stellate cells in collagen production are involved during acute pancreatitis and possibly that these can become active cells through the action of angiotensin II produced by rennin-angiotensin system. However it has been suggested an increasingly close relationship between the RAS and the inflammatory process in this sense these studies indicate a relationship of therapy used to treat hypertension is also feasible in other disorders such as inflammatory problems.

Hypertension and Renin-Angiotensin System 93

Agarwal N, Pitchumoni CS. Acute pancreatitis: a multisystem disease. Gastrenterologist.

Bachem MG, Schneider E, Groß H, Weidenbach H, Schmid RM, Menke A, Siech M, Beger H,

Barros,R., Ramalho, FS e Ramalho, LN. The effect of anti-hypertensive drugs on the obstructive pancreatitis in rats. *Acta Cirurgica Brasileira* 2010, 25:396 - 400 Beierwaltes WH. The role of calcium in the regulation of renin secretion. *Am J Physiol Renal* 

Chan WP, Fung ML, Nobiling R, Leung PS. Activation of local rennin- angiotensin system

Chappell MC, Millsted A, Diz DI, Brosnihan KB, Ferrario CM: Evidence for an intrinsic angiotensin system in the canine pancreas. *J Hypertens* 1991, 9:751-759. De Gasparo M, Catt KJ, Inagami T, Wright JW, Unger TH. The angiotensin II receptors.

Donoghue,M., Hsieh,F., Baronas, E., *et al*. A novel angiotensin –converting enzyme related

Goldman and Gilman. The Pharmacological Basis Therapeutics. The Ed. MacGraw – Hill

Graninger M., Reiter R., Drucker C., Minar E., Jilma B. "Angiotensin receptor blockade

Hackenthal E, Paul M, Ganten D, Taugner R. Morphology, physiology, and molecular

Hama K, Ohnishi H, Yasuda H, Ueda N, Mashima H, Satoh Y, Hanat-suka K, Kita H,

Ip SP, Kwan PC, Williams CH, Pang S, Hooper NM, Leung PS. Changes of angiotensin –

Jacoby D.S. and Rader D.J. "Renin-angiotensin system and atherothrombotic disease: from

Leung PS, Chan HC & Wong PYD. Immunohistochemical localization of angiotensin II in

Leung PS, Chan WP, Wong TP, Sernia C Expression and localization of renin–angiotensin system in the rat pancreas. Journal of Endocrinology 1999, 160:13–19. Leung PS, Carlsson PO. Tissue renin–angiotensin system: its expression, localization, regulation and potential role in the pancreas. J Mol Endocrinol 2000, 166:121–8. Montecucco F., Pende A., Mach F. The Renin-Angiotensin SystemModulates Inammatory

carboxypeptidase (ACE2) convert angiotensin 1 to angiotensin (1-9). Circ. Res.,

decreasesmarkers of vascular inammation," Journal of Cardiovascular

Ohashi A, Tamada K, Sugano K. Angiotensin II stimulates DNA synthesis of rat pancreatic stellate cells by activating ERK through EGF receptor transactivation.

converting enzyme activity in the pancreas of chronic hypoxia and acute

genes to treatment," Archives of Internal Medicine, vol. 163, no. 10, pp. 1155–1164,

Processes in Atherosclerosis: Evidence from Basic Research and Clinical Studies.

stellate cells in rats and humans. *Gastroenterology* 1998, 115:421-432.

by chronic hypoxia. Molec Cell Endocrinol. 2000;160:107-14

biology of rennin secretion. *Physiol Rev.* 1990;4:1067-116.

Bio-chem Biophys Res. Commun 2004, 315:905-911.

pancreatitis. Int J Biochem Cell Biol. 2003;35:944-54.

Mediators of Inammation, 2009, 1-13.

the mouse pancreas. Histochemical Journal 1998, 30: 21–25.

Grünert A, Adler G. Identification, culture, and characterisation of pancreatic

**6. References** 

1993;1:115-28

*Physiol* 2009, 1-36.

2000, 87:E1-E9.

2003.

*Pharmacol Rev.* 2000;52:415-72.

Companies, 11ªedition. 2007

Pharmacology 2004, 44:335–339.

Fig. 3. Comparison of the number of pancreatic stellate cells marked for alpha-smooth muscle actin (α-SMA) and fibrillary acidic protein glial (GFAP), and the percentage of points scored by used. The (PS), between the pancreas of control rats treated with lisinopril and losartan. The bars represent the mean ± SD. \* P <0.001, compared to the treaties.

Fig. 4. Slides stained by hematoxylin and eosin (A) to inflammatory analysis have showed more neutrophylic inflammatory infiltrate in sample of control group measured in [purple]. Moreover slides stained by Sirius red (B) have showed more collagen deposit in the animals of control group too showed in [eosinofilic]. In the group treated (C) and stained by immunohistochemical staining method (GFAP or α-SMA) have less PSCs activated marked in [blue] compared with animals control (D and E) which have more PSCs activated measured in [red] (p<0.05)

#### **6. References**

92 Antihypertensive Drugs

Fig. 3. Comparison of the number of pancreatic stellate cells marked for alpha-smooth muscle actin (α-SMA) and fibrillary acidic protein glial (GFAP), and the percentage of points scored by used. The (PS), between the pancreas of control rats treated with lisinopril and

Fig. 4. Slides stained by hematoxylin and eosin (A) to inflammatory analysis have showed more neutrophylic inflammatory infiltrate in sample of control group measured in [purple]. Moreover slides stained by Sirius red (B) have showed more collagen deposit in the animals

of control group too showed in [eosinofilic]. In the group treated (C) and stained by immunohistochemical staining method (GFAP or α-SMA) have less PSCs activated marked in [blue] compared with animals control (D and E) which have more PSCs activated

measured in [red] (p<0.05)

losartan. The bars represent the mean ± SD. \* P <0.001, compared to the treaties.


**6** 

*Japan* 

Yoshihiro Uesawa

*Meiji Pharmaceutical University,* 

**Pharmacokinetic Interactions of** 

**Antihypertensive Drugs with Citrus Juices** 

It has been known that citrus juices cause pharmaceutical interactions with various kinds of medications. The citrus juice interactions are broadly divided into 2 types which are with increasing and decreasing of drug concentrations in plasma. That is, both types are categorized into pharmacokinetic interactions. In the "increasing" type interactions, grapefruit juice is the most important in the juices. Grapefruit juice makes an increase in the plasma drug concentrations due to the suppression of intestinal metabolization of the drugs. Since the danger of concomitant administration of drugs and grapefruit juice was discovered in 1989, drinking of the juice has been controlled in patients undergoing pharmaceutical therapies. The targeted medications for the restriction ranges from antilipemics to immunosuppressants. Antihypertensive drugs are one of the typical categories of drugs affected by such interaction. A feature of said drugs is that they are characterized as substrates of Cytochrome P-450 3A, the most important-drug metabolizing enzyme in the intestines. Dihydropyridine calcium channel antagonists, as well as verapamil in the antihypertensive drugs was representative of drug categories with such property. In this chapter, grapefruit juice interactions were described, and the latest knowledge presented, as a results of research utilizing statistical investigations with dihydropyridines. On the other hand, information about the "decreasing" type of interactions has been reported in a limited number of research results. Some clinical studies related to β-adrenergic-blocking agents (antihypertensives) such as celiprolol as well as fexofenadine (antihistamine), it was discovered that citrus juices such as orange juice and grapefruit juice reduce intestinal absorption of the drugs. In this chapter, results of the studies of the interactions are explained; and the research attributing an important

ingredient in orange juice in the interaction with the β-blocker, is described.

**2. Grapefruit juice interactions related to the increase of plasma drug** 

In 1989, Bailey and colleagues used grapefruit juice (GFJ) to mask the taste of alcohol in a clinical trial of the interaction between alcohol and drugs. They found that plasma felodipine levels were higher in subjects given GFJ (Bailey, 1989); and in 1991, they published a similar work on both felodipine and nifedipine (Bailey, 1991). At present, GFJ must be avoided in patients receiving certain drugs to prevent this interaction (Figure 1).

**1. Introduction** 

**concentrations** 

