Subscribe Now Subscribe Today
Research Article
 

Evaluation of the Possible Pharmacokinetic Interaction Between Amlodipine, Losartan and Hydrochlorothiazide in Mexican Healthy Volunteers



Noemi Santos-Caballero, Lina Marcela Barranco-Garduno, Jose Carlos Aguilar-Carrasco, Miriam del Carmen Carrasco-Portugal and Francisco Javier Flores-Murrieta
 
Facebook Twitter Digg Reddit Linkedin StumbleUpon E-mail
ABSTRACT

The fixed-dose combinations of drugs are alternatives for a major control of chronical diseases such hypertension. Amlodipine, losartan and hydrochlorothiazide are widely used as pharmacological treatment of this cardiovascular disorder. Since these drugs have different mechanism of action, it could be assumed that a fixed-dose combination containing them will provide therapeutic advantages and greater adherence to the treatment. However, firstly is necessary to verify a possible pharmacokinetic interaction between the components. In this study, the oral pharmacokinetics of amlodipine, losartan and hydrochlorothiazide in a fixed-dose combination formulation were evaluated and compared against the individual components in 26 healthy volunteers. After an overnight fast subjects received an oral dose of losartan (50 mg), hydrochlorothiazide (12.5 mg), amlodipine (5 mg) or the same doses in fixed-dose combination formulation in four periods according to a randomized crossover design. Blood samples were obtained at selected times for a period of 72 h. Plasma was obtained and stored frozen at -80°C until analyzed by ultra performance liquid chromatography coupled with tandem mass spectrometry. The treatments were well tolerated. No changes were observed in the pharmacokinetic parameters of amlodipine. For losartan and losartan acid the plasma levels were slightly higher whereas for hydrochlorothiazide greatly increase more than twice their plasma levels with fixed-dose combination formulation. These results suggest pharmacokinetic interactions between these compounds. Further studies are necessary in order to establish the mechanisms of these interactions, however, clinical relevance should be evaluated in clinical studies in patients in which this fixed-dose combination formulation could be a therapeutic alternative.

Services
Related Articles in ASCI
Search in Google Scholar
View Citation
Report Citation

 
  How to cite this article:

Noemi Santos-Caballero, Lina Marcela Barranco-Garduno, Jose Carlos Aguilar-Carrasco, Miriam del Carmen Carrasco-Portugal and Francisco Javier Flores-Murrieta, 2016. Evaluation of the Possible Pharmacokinetic Interaction Between Amlodipine, Losartan and Hydrochlorothiazide in Mexican Healthy Volunteers. International Journal of Pharmacology, 12: 101-107.

DOI: 10.3923/ijp.2016.101.107

URL: https://scialert.net/abstract/?doi=ijp.2016.101.107

INTRODUCTION

Raised blood pressure or hypertension is one of the most critical risk factors in the development and progressive cardiovascular disease (Weber et al., 2004; Yusuf et al., 2004; WHO., 2011). Hypertension is an haemodynamic disorder in which the blood pressure values are ≥140/90 mm Hg for systolic/dyastolic blood pressures and it is classified in different grades in function of the value measured (WHO., 2011; Stephan et al., 2015). This disorder leads to an increase in morbility and mortality of patients not adequately controlled (James et al., 2014). There are several classes of drugs designed to maintain blood pressure values lower. In order to arrive to this goal, it has been suggested to start with an antihypertensive drug, if the goal is not reached, addition of another antihypertensive drug is recommended and if the blood pressure is not controlled with the use of two antihypertensive drugs, three agents should be used (Amar et al., 2002; Mancia et al., 2004; James et al., 2014). Under these situation, in order to achieve a therapeutic synergism it has been recommended that agents producing their antihypertensive action through different mechanisms of action should be employed (Sever and Messerli, 2011; Wang et al., 2014). A rationale combination may include a calcium antagonist, an angiotensin II receptor antagonist and a diuretic (Waeber et al., 2009). That is why, a new fixed dose combination has been developed, including amlodipine (AML), losartan (LOS) and hydrochlorothiazide (HCTZ).

Amlodipine produces its vasodilatation effect through the inhibition of calcium channels on vascular smooth muscle cells. After an oral administration, its bioavailability is high due to a lower hepatic extraction ratio, the maximum plasma concentration (Cmax) is reached between 6 and 12 h, it is extensively metabolized by the liver (90%) to inactive metabolites and it has a long elimination half-life (30-50 h) (Beresford et al., 1988; Haria and Wagstaff, 1995).

The LOS is an angiotensin II receptor antagonist (Wong et al., 1991). Angiotensin II is involved in blood pressure control, cardiovascular functions as well as sodium and water homeostasis (Meredith, 2005). Blocking the binding of angiotensin II to its receptor in the vascular smooth muscle avoid the vasoconstriction (Keating, 2009). After its oral administration the bioavailability of LOS is close to 33%, is metabolized to losartan carboxylic acid (LOS-A) through CYP2C9 and CYP3A4 enzymes, this metabolite possess major therapeutic activity than parent compound (Lo et al., 1995). The mean time to reach Cmax of LOS and LOS-A are about 1 h and 3-4 h after its administration, respectively (Ohtawa et al., 1993; Lo et al., 1995; Stearns et al., 1995). The terminal half life of LOS and LOS-A are around 2 and 6 to 9 h, respectively (Ohtawa et al., 1993; Lo et al., 1995; Tamaki et al., 1997).

Hydrochlorothiazide (HCTZ) is a diuretic widely used in clinical practice since several years ago as individual or in FDC formulation for hypertension treatment (Wellington and Faulds, 2002). This drugs acts blocking the reabsorption of sodium in the renal tubules which contributes to increase the elimination of this electrolyte and turn favors the reduction of extracellular fluid volume and peripheral resistance (Meredith, 2005). After its oral administration, it has a bioavailability ranged from 60-70%. The time to achieve peak plasma concentration occur between 1.5-4 h after the administration. This drug is excreted unchanged in the urine and its elimination half life is around 8-10 h (Welling, 1986).

Since the mentioned drugs have different mechanism of action which can considered as complementary for the treatment of hypertension, the design of a FDC formulation is an attractive alternative for therapeutic purposes. However, before the therapeutic responses are evaluated, is necessary to verify if pharmacokinetic properties of each compound are not altered in the FDC formulation. The aim of this study was to evaluate the oral pharmacokinetics of AML, LOS and HCTZ in a FDC formulation and compared against the individual components in healthy volunteers.

MATERIAL AND METHODS

Study design: This was a randomized, open-label, single-dose, four-treatment, four-periods, four-sequences study. Healthy Mexican adults aged between 18 and 55 years of either sex, with a body mass index of 20-26 kg m–2 and with no congenital abnormalities or chronic diseases were elegible for inclusión. Volunteers gave written informed consent for participation in the study, according to the protocol approved by the Institutional Ethics Committee and following the recommendations of the declaration of Helsinki. Physical examination, clinical history and suitable laboratory tests were carried out for each subject. Subjects were excluded if they had a history of clinically significant medical conditions, alcohol abuse or ilegal drugs use, smoked more than 10 cigarettes per day, as well as if laboratory tests values were significantly out of reference range. Volunteers selected were randomized to receive either of the four sequences established.

After an overnight fast, subjects received, alternatively, an oral single dose of FDC formulation containing AML 5 mg, LOS 50 mg and HCTZ 12.5 mg or an oral single dose of each compound alone (plus placebo) in individual formulation at the same doses of FDC formulation given with 250 mL of water.

Heparinized blood samples (12 mL) were obtained immediately before and at 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 10, 24, 48 and 72 h after drugs administration. The washout period between the treatments was two weeks. Plasma was obtained by centrifugation of blood samples and stored frozen at -80̊C until analyzed for drugs concentrations by high-performance liquid chromatogry coupled to mass/mass spectrometry.

Determination of drugs in plasma: Plasma levels of AML, LOS, LOS-A and HCTZ were determined by high-performance liquid chromatography coupled to a mass/mass spectrophotometer. All validation tests were carried out according to the Mexican Official Norm (1998).

Amlodipine: Firstly, plasma samples were alkalinized. Amlodipine and internal standard (dexamethasone) were extracted by liquid-liquid extraction with a mixture of diethyl ether, hexane and dichlorometane. Organic layer was evaporated to dryness and dry residue was redissolved and injected into the chromatographic system. Separation of compounds was carried out in a Gemini 5 μm C18 column eluted with a mixture of acetonitrile, methanol and aqueous solution of ammonium acetate. The method was linear in the range of 0.1-20 ng mL–1 and intra and inter-day accuracy (measured as absolute deviation (%)) was lower than 4.81% and coefficient of variation were lower than 9.16%.

Losartan and losartan acid (metabolite): Plasma samples were acidified and drugs were extracted through a solid phase technique. Tolmetin was used as internal standard. Compounds were eluted with a mixture of methanol, acetonitrile and ammonium acetate and injected into the chromatographic system. Separation of compounds was carried out in a Polaris 5 μm C18 column eluted with a mixture of acetonitrile and methanol with an aqueous solution of ammonium acetate and formic acid. The method was linear in the ranges of 5-900 and 15-1500 ng mL–1 for LOS and LOS-A, respectively. The intra and inter-day accuracy (measured as absolute deviation (%)) for LOS was lower than 11.47% and coefficient of variation were lower than 6.82%, whereas for LOS-A were lower than 11.09% and coefficient of variation were lower than 5.94%, for intra and inter-day accuracy and coefficient of variation, respectively.

Hydrochlorothiazide: For the analysis of HCTZ, plasma samples were previously acidified and paracetamol was used as internal standard. Drugs were extracted through a liquid-liquid technique using a mixture of diethyl ether and dichlorometane. Organic layer was evaporated to dryness and dry residue was redissolved and injected into the chromatographic system. Separation of compounds was carried out in a Sielc Primesep D 100 Å column eluted with a mixture of acetonitrile and aqueous mixture solution of formic acid and ammonium acetate. Under these conditions, the method was linear in the range of 1-400 ng mL–1 and intra and inter-day accuracy (measured as absolute deviation (%)) was lower than 5.98% and coefficient of variation was lower than 6.85%.

Under these conditions, each analytical method was suitable for conducting pharmacokinetic studies of AML, LOS, LOS-A and HCTZ.

Pharmacokinetic and statistical analysis: Individual plasma-level time curves were constructed for each formulation. The maximal concentration (Cmax) and time to reach this maximum (tmax) were directly obtained from these curves. Area under the plasma concentration against time curve until the last sampling time (AUCt) was obtained by the trapezoidal rule (Rowland and Tozer, 1989). Area under the curve extrapolated to infinity (AUC) was obtained by the sum of AUCt plus extrapolation to infinity, obtained by dividing the last concentration by the terminal elimination rate constant (Ke). Half-life (t1/2) was obtained by diving ln2/ke. All parameters were obtained using the WinNonlin Professional ver. 2.1 software (Pharsight, Palo Alto, CA and USA).

RESULTS

A total of twenty-eight Mexican healthy male and female were enrolled. Among them, two volunteers abandoned the study. The study was completed by twenty-six subjects weighing (Mean±S.D) 66.03±10.71 kg, 1.62±0.09 m in height and 35.48±9.52 years of age were included in the study. Treatments were well tolerated and no important adverse events were observed.

The mean (s.e.m.) drug plasma concentration-time profiles obtained after the oral administration of the formulations in study are shown in Fig. 1-4. Figure 1 shown similar pharmacokinetic profile of AML between both formulations. Plasma levels are kept very close both absorption and elimination phases. As Fig. 2 showed the profiles obtained for LOS. It can be seen that during absorption phase the plasma levels from both formulations reaches its Cmax in similar manner. However, the profiles change during decay phase in which the plasma levels are slightly higher for FDC formulation.

Image for - Evaluation of the Possible Pharmacokinetic Interaction Between Amlodipine, Losartan and Hydrochlorothiazide in Mexican Healthy Volunteers
Fig. 1:
Amlodipine (AML) plasma concentration against time curves after administration of an oral dose of 5 mg in two pharmaceutical formulations. Individual tablets of amlodipine 5 mg (black circles) and FDC formulation of amlodipine 5 mg, losartan 50 mg and hydrochlorothiazide 12.5 mg (white circles) to 26 healthy volunteers. Data are expressed as Mean±SEM

Image for - Evaluation of the Possible Pharmacokinetic Interaction Between Amlodipine, Losartan and Hydrochlorothiazide in Mexican Healthy Volunteers
Fig. 2:
Losartan (LOS) plasma concentration against time curves after administration of an oral dose of 50 mg in two pharmaceutical formulations. Individual capsules of losartan 50 mg (black circles) and FDC formulation of amlodipine 5 mg, losartan 50 mg and hydrochlorothiazide 12.5 mg (white circles) to 26 healthy volunteers. Data are expressed as Mean±SEM

Similarly, LOS-A from the FDC formulation achieves higher concentrations than LOS alone formulation which are more evident at tmax and in the initial decay phase as shown in Fig. 3. Finally, the pharmacokinetic profiles of HCTZ are depicted in Fig. 4. In this case the co-administration of this compound with AML and LOS greatly increase more than twice their plasma levels. The mean pharmacokinetic parameters of each compound by formulation are shown in Table 1.

Image for - Evaluation of the Possible Pharmacokinetic Interaction Between Amlodipine, Losartan and Hydrochlorothiazide in Mexican Healthy Volunteers
Fig. 3:
Losartan acid (LOS-A) plasma concentration against time curves after administration of an oral dose of 50 mg of losartan in two pharmaceutical formulations. Individual capsules of losartan 50 mg (black circles) and FDC formulation of amlodipine 5 mg, losartan 50 mg and hydrochlorothiazide 12.5 mg (white circles) to 26 healthy volunteers. Data are expressed as Mean±SEM

Image for - Evaluation of the Possible Pharmacokinetic Interaction Between Amlodipine, Losartan and Hydrochlorothiazide in Mexican Healthy Volunteers
Fig. 4:
Hydrochlorothiazide (HCTZ) plasma concentration against time curves after administration of an oral dose of 12.5 mg in two pharmaceutical formulations. Individual capsules of hydrochlorothiazide 12.5 mg (black circles) and FDC formulation of amlodipine 5 mg, losartan 50 mg and hydrochlorothiazide 12.5 mg (white circles) to 26 healthy volunteers. Data are expressed as Mean±SEM

DISCUSSION

Hypertension monotherapy may become not sufficient for some patients, being required the coadministration of two or more drugs to achieve appropriate blood pressure control. However, patient adherence during polypharmacy or complex treatment regimens are major factors to detrimental therapeutic goal among patients with hypertension (Erdine, 2010; Bangalore and Ley, 2012).

Table 1: Pharmacokinetic parameters of amlodipine (AML), losartan (LOS), losartan acid (LOS-A) and hydrochlorothiazide (HCTZ) after the administration of an oral single dose of the formulations in study to 26 healthy volunteers
Image for - Evaluation of the Possible Pharmacokinetic Interaction Between Amlodipine, Losartan and Hydrochlorothiazide in Mexican Healthy Volunteers
Cmax: Maximum plasma concentration, tmax: Maximum time, AUCo-t: Area under the plasma concentration, AUC: Area under curve extrapolated to infinity, t1/2: Half-life, AML: Amlodipine, LOS: Losartan, HCTZ: Hydrochlorothiazide, FDC: Fixed dose combination, Data are expressed as Mean±SEM

This can be solved by the use of once-daily dosing containing two or more compounds, that is, by using FDC formulation. The main advantages of this type of pharmaceutical alternatives are: Improving patient adherence by regimen simplification, to reduce pill burden, optimizing care and lower medical cost (Frantz, 2006; Erdine, 2010; Angeli et al., 2012; Bangalore and Ley, 2012). However, in order to obtain a formulation with adequate biopharmaceutical properties, features such as solubility, drug release, reactivity and stability between the components are needed to be considered during the design and development of this type of pharmaceutical formulation (Frantz, 2006). Additionally, another aspect to be considered previous to a new FDC become available is to establish if pharmacokinetic interaction between the components is present.

This study shows that the co-administration of AML, LOS and HCTZ in a new FDC formulation causes an increase in the bioavailabilities of HCTZ and lesser extent in LOS and its metabolite, whereas for AML it was not observed any modification. Since all formulations tested in this study were manufactured with the same excipients, a possible drug-formulation interaction can be ruled out. Rather, our results suggests a possible pharmacokinetic interaction that affect the systemic exposure to HCTZ and LOS. It has been established that pharmacokinetic drug-drug interaction refers to an alteration of the concentration of one drug caused by the presence of a second drug through effects on absorption, distribution, metabolism or excretion (Grasela et al., 1987; Fleisher et al., 1999).

As it observed, HCTZ, LOS and LOS-A AUCt and AUC values from FDC formulation were higher in comparison with those obtained for each compound alone. According with these results, in this study faced two scenarios: (i) AML or HCTZ influence on the oral parmacokinetics of LOS and (ii) AML or LOS influences on the oral pharmacokinetics of HCTZ.

Since there are not evidence about LOS or HCTZ induce or inhibit significantly the metabolism of other drugs, interaction at metabolic process due these agents is unlikely. In the case of AML, there are reports that indicate a competitive inhibition of the CYP3A4 metabolic activity (Son et al., 2014). Losartan (LOS) is partially metabolized by CYP3A4, if a competitive inhibition was carried out between AML and LOS, the LOS-A/LOS Cmax and AUCt ratios were minor for the FDC formulation in comparison with those obtained for LOS alone. In this study, they were slightly higher, which indicates that the increase in the Cmax and AUCt of LOS-A is a direct result due to the increase of LOS concentrations possibly related to the absorption process as reviewd below. Thus, AML does not affect the metabolic process of LOS. In the case of the greater bioavailability of HCTZ observed with FDC formulation, this can be explained by a different mechanism of metabolic process since HCTZ is excreted unchanged in the urine (Beermann and Groschinsky-Grind, 1977).

Other possible mechanism to consider in a drug-drug interaction occur during distribution pharmacokinetic process. It has been established that when a drug is displaced from its protein-binding sites, its concentration and its metabolic rate increase (Fan and de Lannoy, 2014). However, for this condition it is necessary that the coadministered drugs have higher affinity to plasma proteins. Amlodipine has a high degree of protein binding (98%) (Meredith and Elliot, 1992), whereas LOS and LOS-A are highly bound to plasmatic protein (98.8 and 99.7%, respectively), additionally, in vitro studies showed neither LOS or LOS-A were displaced by pharmacologically concentrations of drugs with high degree of protein binding such as non-steroidal anti-inflammatory drugs, warfarin or diazepam, thus, displacement of LOS from binding sites are unlikely (Christ, 1995). Hydrochlorothiazide has lower extent of protein binding (40-68%) (Beermann and Groschinsky-Grind, 1977), therefore, a mechanism of this type can not be ruled out since AML and LOS have high affinity to protein binding and they could displace HCTZ. However, there are previous reports were FDC formulations containing LOS and HCTZ were evaluated for safety and efficacy and were well-tolerated (McCrea et al., 1995; Keating, 2009) and no evidence of pharmacokinetic drug interaction was observed (McCrea et al., 1995). Thereby, the presence of AML appears to play an important role in our results. However, further evaluation is thus warranted.

Regarding a possible interaction at absorption site, it has been recognized that the presence of transporters at the apical surface of small intestinal play significant roles in determining the drug bioavailability, therefore, it is necessary to consider for drug-drug interaction (You and Morris, 2007). There is evidence that calcium channel antagonists are modulators to a variable degree of P-glycoprotein efflux transporter (Sharom, 2007). In fact, it has been reported the potential of AML to inhibit the efflux activity of this transporter (Katoh et al., 2000; Zhou et al., 2013). This inhibitory activity could help to explain the increase in the bioavailabilities of LOS and HCTZ since there are evidence suggesting LOS and HCTZ are substrates of this transporter (Hayeshi et al., 2006; Choi et al., 2010, 2013; Liao et al., 2010; Yang et al., 2011). In this study the dose of AML in FDC formulation is low, according with this, is possible that the impact on the oral bioavailability of LOS is modest but significant. In the case of HCTZ the differences between the bioavailabilites are much greater, a combination of pharmacokinetic interaction at different sites could explain such differences. Moreover, it has reported the HCTZ absorption is greater at pH 6 than pH 7.4 (Liao et al., 2010), thus a possible alteration of physiological pH by the presence of AML and/or LOS could be not ruled out.

CONCLUSION

In conclusion, this study shows that the coadministration of AML, LOS and HCTZ in a new FDC formulation or the administration of each drug alone to healthy Mexican volunteers were well-tolerated. However, it was observed an increase in the systemic exposure to LOS and LOS-A as well as to HCTZ after the administration of FDC formulation. Further studies are necessary in order to establish the mechanisms of these pharmacokinetic drug-drug interactions.

REFERENCES

1:  Amar, J., L. Vaur, M. Perret, C. Bailleau, S. Etienne and B. Chamontin, 2002. Hypertension in high-risk patients: Beware of the underuse of effective combination therapy (results of the PRATIK study). J. Hypertension, 20: 779-784.
Direct Link  |  

2:  Angeli, F., G. Reboldi, G. Mazzotta, M. Garofoli, E. Ramundo, C. Poltronieri and P. Verdecchia, 2012. Fixed-dose combination therapy in hypertension. High Blood Pressure Cardiovasc. Prevent., 19: 51-54.
CrossRef  |  Direct Link  |  

3:  Bangalore, S. and L. Ley, 2012. Improving treatment adherence to antihypertensive therapy: The role of single-pill combinations. Expert Opin. Pharmacother., 13: 345-355.
CrossRef  |  Direct Link  |  

4:  Beermann, B. and M. Groschinsky-Grind, 1977. Pharmacokinetics of hydrochlorothiazide in man. Eur. J. Clin. Pharmacol., 12: 297-303.
CrossRef  |  Direct Link  |  

5:  Beresford, A.P., D. McGibney, M.J. Humphrey, P.V. Macrae and D.A. Stopher, 1988. Metabolism and kinetics of amlodipine in man. Xenobiotica: Fate Foreign Compounds Biol. Syst., 18: 245-254.
CrossRef  |  Direct Link  |  

6:  Choi, D.H., C. Li and J.S. Choi, 2010. Effects of myricetin, an antioxidant, on the pharmacokinetics of losartan and its active metabolite, EXP‐3174, in rats: Possible role of cytochrome P450 3A4, cytochrome P450 2C9 and P‐glycoprotein inhibition by myricetin. J. Pharm. Pharmacol., 62: 908-914.
CrossRef  |  Direct Link  |  

7:  Choi, J.S., J. Choi and D.H. Choi, 2013. Effects of licochalcon A on the pharmacokinetics of losartan and its active metabolite, EXP-3174, in rats. Die Pharmazie Int. J. Pharm. Sci., 68: 882-888.
CrossRef  |  Direct Link  |  

8:  Christ, D.D., 1995. Human plasma protein binding of the angiotensin II receptor antagonist losartan potassium (DuP 753/MK 954) and its pharmacologically active metabolite EXP3174. J. Clin. Pharmacol., 35: 515-520.
CrossRef  |  Direct Link  |  

9:  Erdine, S., 2010. Compliance with the treatment of hypertension: The potential of combination therapy. J. Clin. Hyperten., 12: 40-46.
CrossRef  |  Direct Link  |  

10:  Fan, J. and I.A.M. de Lannoy, 2014. Pharmacokinetics. Biochem. Pharmacol., 87: 93-120.
CrossRef  |  Direct Link  |  

11:  Fleisher, D., C. Li, Y. Zhou, L.H. Pao and A. Karim, 1999. Drug, meal and formulation interactions influencing drug absorption after oral administration. Clin. Pharm., 36: 233-254.
CrossRef  |  Direct Link  |  

12:  Frantz, S., 2006. The trouble with making combination drugs. Nat. Rev. Drug Discov., 5: 881-882.
CrossRef  |  Direct Link  |  

13:  Grasela, T.H., E.J. Antal, L. Ereshefsky, B.G. Wells, R.L. Evans and R.B. Smith, 1987. An evaluation of population pharmacokinetics in therapeutic trials. Part II. Detection of a drug‐drug interaction. Clin. Pharmacol. Therapeut., 42: 433-441.
CrossRef  |  Direct Link  |  

14:  Haria, M. and A.J. Wagstaff, 1995. Amlodipine. A reappraisal of its pharmacological properties and therapeutic use in cardiovascular disease. Drugs, 50: 560-586.
PubMed  |  Direct Link  |  

15:  Hayeshi, R., C. Masimirembwa, S. Mukanganyama and A.L.B. Ungell, 2006. The potential inhibitory effect of antiparasitic drugs and natural products on P-glycoprotein mediated efflux. Eur. J. Pharm. Sci., 29: 70-81.
CrossRef  |  Direct Link  |  

16:  James, P.A., S. Oparil, B.L. Carter, W.C. Cushman and C. Dennison-Himmelfarb et al., 2014. 2014 evidence-based guideline for the management of high blood pressure in adults: Report from the panel members appointed to the Eighth Joint National Committee (JNC 8). J. Am. Med. Assoc., 311: 507-520.
CrossRef  |  Direct Link  |  

17:  Katoh, M., M. Nakajima, H. Yamazaki and T. Yokoi, 2000. Inhibitory potencies of 1, 4-dihydropyridine calcium antagonists to P-glycoprotein-mediated transport: Comparison with the effects on CYP3A4. Pharm. Res., 17: 1189-1197.
CrossRef  |  Direct Link  |  

18:  Keating, G.M., 2009. Losartan/Hydrochlorothiazide: A review of its use in the treatment of hypertension and for stroke risk reduction in patients with hypertension and left ventricular hypertrophy. Drugs, 69: 1239-1265.
CrossRef  |  Direct Link  |  

19:  Liao, X.H., J.J. Wang, M.Y. Gao, Q. Gao and Y. Chen, 2010. [Effect of major components of maijunan tablets on the transport of hydrochlorothiazide in Caco-2 cell monolayer model]. Acta Pharmaceut. Sinica, 45: 104-108.
PubMed  |  Direct Link  |  

20:  Lo, M.W., M.R. Goldberg, J.B. McCrea, H. Lu, C.I. Furtek and T.D. Bjornsson, 1995. Pharmacokinetics of losartan, an angiotensin II receptor antagonist and its active metabolite EXP3174 in humans. Clin. Pharmacol. Ther., 58: 641-649.
CrossRef  |  Direct Link  |  

21:  Mancia, G., A.C. Pessina, B. Trimarco and G. Grassi, 2004. Blood pressure control according to new guidelines targets in low-to high-risk hypertensives managed in specialist practice. J. Hypertens., 22: 2387-2396.
Direct Link  |  

22:  McCrea, J.B., M.W. Lo, L. Tomasko, C.C. Lin, J.Y.K. Hsieh, N.L. Capra and M.R. Goldberg, 1995. Absence of a pharmacokinetic interaction between losartan and hydrochlorothiazide. J. Clin. Pharmacol., 35: 1200-1206.
CrossRef  |  Direct Link  |  

23:  Meredith, P.A., 2005. Angiotensin II receptor antagonists alone and combined with hydrochlorothiazide. Am. J. Cardiovasc. Drugs, 5: 171-183.
CrossRef  |  Direct Link  |  

24:  Meredith, P.A. and H.L. Elliott, 1992. Clinical pharmacokinetics of amlodipine. Clin. Pharm., 22: 22-31.
CrossRef  |  Direct Link  |  

25:  Mexican Official Norm, 1998. Tests and procedures to prove that a medication is interchangeable. Mexican Official Norm, NOM-177-SSA1-1998, Requirement 9.1, Official Journal of the Federation, May 7, 1999, Mexico City, Mexico. http://www.salud.gob.mx/unidades/cdi/nom/177ssa18.html.

26:  Ohtawa, M., F. Takayama, K. Saitoh, T. Yoshinaga and M. Nakashima, 1993. Pharmacokinetics and biochemical efficacy after single and multiple oral administration of losartan, an orally active nonpeptide angiotensin II receptor antagonist, in humans. Br. J. Clin. Pharmacol., 35: 290-297.
CrossRef  |  Direct Link  |  

27:  Rowland, M. and T.N. Tozer, 1989. Clinical Pharmacokinetics: Concepts and Applications. 3rd Edn., Lea and Febiger, Philadelphia, USA

28:  Sever, P.S. and F.H. Messerli, 2011. Hypertension management 2011: Optimal combination therapy. Eur. Heart J., 32: 2499-2506.
CrossRef  |  Direct Link  |  

29:  Sharom, F., 2007. Multidrug Resistance Protein: P-glycoprotein. In: Drug Transporters: Molecular Characterization and Role in Drug Disposition, You, G. and M.E. Morris (Eds.). Wiley, New York, ISBN: 9780470140499, pp: 223-262

30:  Son, H., D. Lee, L.A. Lim, S.B. Jang, H. Roh and K. Park, 2014. Development of a pharmacokinetic interaction model for co-administration of simvastatin and amlodipine. Drug Metab. Pharm., 29: 120-128.
CrossRef  |  Direct Link  |  

31:  Stearns, R.A., P.K. Chakravarty, R. Chen and S.H. Chiu, 1995. Biotransformation of losartan to its active carboxylic acid metabolite in human liver microsomes. Role of cytochrome P4502C and 3A subfamily members. Drug Metab. Dispos., 23: 207-215.
Direct Link  |  

32:  Stephan, D., S. Gaertner and E.M. Cordeanu, 2015. A critical appraisal of the guidelines from France, the UK, Europe and the USA for the management of hypertension in adults. Arch. Cardiovasc. Dis., 108: 453-459.
CrossRef  |  Direct Link  |  

33:  Tamaki, T., A. Nishiyama, S. Kimura, Y. Aki and M. Yoshizumi et al., 1997. EXP3174: The major active metabolite of losartan. Cardiovasc. Drug Rev., 15: 122-136.
CrossRef  |  Direct Link  |  

34:  Waeber, B., F. Feihl and L.M. Ruilope, 2009. Fixed-dose combinations as initial therapy for hypertension: A review of approved agents and a guide to patient selection. Drugs, 69: 1761-1776.
CrossRef  |  Direct Link  |  

35:  Wang, T.D., Y.H. Chen, C.H. Huang, W.J. Chen and M.F. Chen, 2014. Bidirectional adherence changes and associated factors in patients switched from free combinations to equivalent single-pill combinations of antihypertensive drugs. Hypertension, 63: 958-967.
CrossRef  |  PubMed  |  Direct Link  |  

36:  Weber, M.A., S. Julius, S.E. Kjeldsen, H.R. Brunner and S. Ekman et al., 2004. Blood pressure dependent and independent effects of antihypertensive treatment on clinical events in the VALUE Trial. Lancet, 363: 2049-2051.
CrossRef  |  Direct Link  |  

37:  Welling, P.G., 1986. Pharmacokinetics of the thiazide diuretics. Biopharmaceut. Drug Disposit., 7: 501-535.
CrossRef  |  Direct Link  |  

38:  Wellington, K. and D.M. Faulds, 2002. Valsartan/hydrochlorothiazide: A review of its pharmacology, therapeutic efficacy and place in the management of hypertension. Drugs, 62: 1983-2005.
PubMed  |  Direct Link  |  

39:  WHO., 2011. Raised Blood Pressure (Hypertension): A Major Risk Factor of CVDs. In: Global Atlas on Cardiovascular Disease Prevention and Control, Mendis, S., P. Puska and B. Norrving (Eds.). WHO Press, USA., pp: 38-39

40:  Wong, P.C., T.B. Barnes, A.T. Chiu, D.D. Christ, J.V. Duncia, W.F. Herblin and P.B. Timmermans, 1991. Losartan (DuP 753), an orally active nonpeptide angiotensin II receptor antagonist. Cardiovasc. Drug Rev., 9: 317-339.
CrossRef  |  Direct Link  |  

41:  Yang, S.H., J.S. Choi and D.H. Choi, 2011. Effects of HMG-CoA reductase inhibitors on the pharmacokinetics of losartan and its main metabolite EXP-3174 in rats: Possible role of CYP3A4 and P-gp inhibition by HMG-CoA reductase inhibitors. Pharmacology, 88: 1-9.
CrossRef  |  Direct Link  |  

42:  You, G. and M.E. Morris, 2007. Overview of Drug Transporter Families. In: Drug Transporters: Molecular Characterization and Role in Drug Disposition, You, G. and M.E. Morris (Eds.). John Wiley and Sons, New York, pp: 1-10

43:  Yusuf, S., S. Hawken, S. Ounpuu, T. Dans and A. Avezum et al., 2004. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): Case-control study. Lancet, 364: 937-952.
CrossRef  |  PubMed  |  Direct Link  |  

44:  Zhou, Y.N., B.K. Zhang, J. Li, X.C. Zuo and H. Yuan et al., 2013. Effect of amlodipine on the pharmacokinetics of tacrolimus in rats. Xenobiotica: Fate Foreign Compounds Biol. Syst., 43: 699-704.
CrossRef  |  Direct Link  |  

©  2021 Science Alert. All Rights Reserved