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Model based population PK-PD analysis of furosemide for BP lowering effect: A comparative study in primary and secondary hypertension
Cent Drug Res Inst, CSIR, Pharmacokinet & Metab Div, Sitapur Rd, Lucknow 226031, Uttar Pradesh, India.;Acad Sci & Innovat Res, Mathura Rd, New Delhi 110025, India..
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Helwan Univ, Dept Pharm Practice, Cairo 11175, Egypt..
Acad Sci & Innovat Res, Mathura Rd, New Delhi 110025, India.;Cent Drug Res Inst, CSIR, Pharmacol Div, Lucknow 226031, Uttar Pradesh, India..
Cent Drug Res Inst, CSIR, Pharmacokinet & Metab Div, Sitapur Rd, Lucknow 226031, Uttar Pradesh, India.;Acad Sci & Innovat Res, Mathura Rd, New Delhi 110025, India..
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2017 (English)In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 109, p. 253-261Article in journal (Refereed) Published
Abstract [en]

Though numerous reports have demonstrated multiple mechanisms by which furosemide can exert its antihypertensive response. However, lack of studies describing PK-PD relationship for furosemide featuring its antihypertensive property has limited its usage as a blood pressure (BP) lowering agent. Serum concentrations and mean arterial BP were monitored following 40 and 80 mg kg(-1) multiple oral dose of furosemide in spontaneously hypertensive rats (SHR) and DOCA-salt induced hypertensive (DOCA-salt) rats. A simultaneous population PK-PD relationship using Emax model with effect compartment was developed to compare the anti-hypertensive efficacy of furosemide in these rat models. A two-compartment PK model with Weibull-type absorption and first-order elimination best described the serum concentration-time profile of furosemide. In the present study, post dose serum concentrations of furosemide were found to be lower than the EC50. The EC50 predicted in DOCA-salt rats was found to be lower (4.5-fold), whereas the tolerance development was higher than that in SHR model. The PK-PD parameter estimates, particularly lower values of EC50, Ke and Q in DOCA-salt rats as compared to SHR, pinpointed the higher BP lowering efficacy of furosemide in volume overload induced hypertensive conditions. Insignificantly altered serum creatinine and electrolyte levels indicated a favorable side effect profile of furosemide. In conclusion, the final PK-PD model described the data well and provides detailed insights into the use of furosemide as an anti-hypertensive agent.

Place, publisher, year, edition, pages
2017. Vol. 109, p. 253-261
Keywords [en]
Furosemide, PK-PD modeling, Blood pressure, Anti-hypertensive, Diuretic, NONMEM
National Category
Pharmacology and Toxicology
Identifiers
URN: urn:nbn:se:uu:diva-340683DOI: 10.1016/j.ejps.2017.08.009ISI: 000413325000027PubMedID: 28821435OAI: oai:DiVA.org:uu-340683DiVA, id: diva2:1180134
Available from: 2018-02-05 Created: 2018-02-05 Last updated: 2018-02-05Bibliographically approved

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