title: Pharmacokinetic-pharmacodynamic analyses of antihypertensive drugs, nifedipine and propranolol, in spontaneously hypertensive rats to investigate characteristics of effect and side effects.
abstract: To investigate the relationship between the pharmacokinetics (PK) and effects and/or side-effects of nifedipine and propranolol, simultaneous examination of their PK and pharmacodynamics (PD), namely blood pressure (BP), heart rate (HR), and QT interval (QT), were assessed in spontaneously hypertensive rats as a disease model. Drugs were infused intravenously for 30 min, then plasma PK and hemodynamic effects were monitored. After general two-compartmental analysis was applied to the plasma data, PD parameters were calculated by fitting the data to PK-PD models. After nifedipine administration, the maximal hypotensive effect appeared about 10 min after starting the infusion, then BP started to elevate although the plasma concentration increased, supposedly because of a negative feedback mechanism generated from the homeostatic mechanism. After propranolol administration, HR decreased by half, and this bradycardic effect was greater than that with nifedipine. Wide variation in QT was observed when the propranolol concentration exceeded 700 ng/mL. This variation may have been caused by arrhythmia. Prolongation of QT with propranolol was greater than that with nifedipine, and bradycardia was slower than the concentration increase and QT prolongation. The characteristically designed PK-PD model incorporating a negative feedback system could be adequately and simultaneously fitted to both observed effect and side-effects.
authors.affiliation: Department of Pharmacokinetics, Faculty of Pharmaceutical Sciences, Doshisha Women's College of Liberal Arts, Kodo, Kyotanabe, Kyoto, 610-0395, Japan. Electronic address: akiriyam@dwc.doshisha.ac.jp.
authors.forename: Akiko
authors.initials: A
authors.lastname: Kiriyama
authors.affiliation: Department of Pharmacokinetics, Faculty of Pharmaceutical Sciences, Doshisha Women's College of Liberal Arts, Kodo, Kyotanabe, Kyoto, 610-0395, Japan.
authors.forename: Akino
authors.initials: A
authors.lastname: Honbo
authors.affiliation: Department of Biopharmaceutics, Faculty of Pharmaceutical Sciences, Doshisha Women's College of Liberal Arts, Kodo, Kyotanabe, Kyoto, 610-0395, Japan.
authors.forename: Asako
authors.initials: A
authors.lastname: Nishimura
authors.affiliation: Department of Biopharmaceutics, Faculty of Pharmaceutical Sciences, Doshisha Women's College of Liberal Arts, Kodo, Kyotanabe, Kyoto, 610-0395, Japan.
authors.forename: Nobuhito
authors.initials: N
authors.lastname: Shibata
authors.affiliation: Department of Pharmacokinetics, Faculty of Pharmaceutical Sciences, Doshisha Women's College of Liberal Arts, Kodo, Kyotanabe, Kyoto, 610-0395, Japan.
authors.forename: Katsumi
authors.initials: K
authors.lastname: Iga
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000319:Adrenergic beta-Antagonists / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity; D001794:Blood Pressure / Q000187:drug effects*; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity; D004195:Disease Models, Animal; D025461:Feedback, Physiological; D006339:Heart Rate / Q000187:drug effects; D006973:Hypertension / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D007262:Infusions, Intravenous; D008297:Male; D008954:Models, Biological; D015233:Models, Statistical; D009543:Nifedipine / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity; D011433:Propranolol / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity; D011918:Rats, Inbred SHR; D018570:Risk Assessment
chemical_list: D000319:Adrenergic beta-Antagonists; D000959:Antihypertensive Agents; D002121:Calcium Channel Blockers; D011433:Propranolol; D009543:Nifedipine
keywords: Antihypertensive drug; Blood pressure; Heart rate; Nifedipine; Pharmacokinetic-pharmacodynamic (PK-PD) modeling; Propranolol; QT interval; Spontaneously hypertensive rat (SHR)