1989 Fiscal Year Final Research Report Summary
Pharmacokinetics and Pharmacodynamics of Antiarrhythmic Drugs in Disease State
| Project/Area Number |
62480431
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| Research Category |
Grant-in-Aid for General Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Research Field |
応用薬理学・医療系薬学
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| Research Institution | KYOTO UNIVERSITY |
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Principal Investigator |
HORI Ryohei Kyoto Univ., Faculty of Med., Professor, 医学部, 教授 (40001036)
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| Co-Investigator(Kenkyū-buntansha) |
SAKURAI Tunetaro Kyoto Univ., Faculty of Med., Lecturer, 医学部, 講師 (80127084)
TANIGAWARA Yusuke Kyoto Univ., Faculty of Med., Instructor, 医学部, 助手 (30179832)
YASUHARA Masato Kyoto Univ., Faculty of Med., Lecturer, 医学部, 講師 (00127151)
KAMIYA Akira Kyoto Univ., Faculty of Med., Lecturer, 医学部, 講師 (90124792)
INUI Ken-ichi Kyoto Univ., Faculty of Med., Assoc. Prof., 医学部, 助教授 (70034030)
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| Project Period (FY) |
1987 – 1989
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| Keywords | Antiarrhythmics / Pharmacokinetics / Pharmacodynamics / Design of dosage regimen / Disease state models / Arrhythmias / Hyperthyroidism / Renal dysfunction |
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| Research Abstract |
Variability in the patients response to antiarrhythaics is a crucial consideration in designing dosage regimens, and the definition of the mechanisms of interindividual variability in drug response is of critical importance. Various .-kinds of disease states affecting the cardiac function may cause significant variations in the kinetics of antiarrhythmic drug action. In the present study, the effects of disease states on both the pharmacokinetics and the pharmacodynazibs of antiarrhythmic drugs were investigated.
1. The relationship between the unbound drug concentration and the pharmacolgic effect was analyzed by a combined pharmacokinetic-pharjeacodyninic model, where the hypothetical effect compartment is connected to the unbound drug concentration in the central compartment by a first-order process. This model allows estimation of the ECG changes after intravenous administration of aimaline.
2. Antiarrhythmic actions of aimaline against ischemia and subsequent reperfusion induced arrhythmias were investigated in anesthetized rats. The beneficial effect of aimaline against reperfusion-induced arrhythmias is related to the ischemic myocardial concentration of ainaline which is markedly affected by the time of drug administration.
3. Aimaline exhibited an increased negative dromotropic activity in hyperthyroid rats compared with control rats. A positive correlation was found between the pacing rate and the dromotropic action of aimaline. Thus, the increased dronotropic activity of ainaline is mainly due to the increased heart rate in hyperthyroid rats.
4. Rats with renal dysfunction showed an increased availability of orally administered ainaline and propranolol. Renal dysfunction was associated with an increased absorption rate from the small intestine. The higher availability of aimaline and in renal dysfunction could be explained at least in part by the increased absorption rate from the intestine and the non-linear extraction in the liver.
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