Abstract
(–)-N-{2-[(R)-3-(6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)piperidino]ethyl}-4-fluorobenzamide (YM758), a novel “funny” If current channel (If channel) inhibitor, is developed as a treatment for stable angina and atrial fibrillation. In this study, the pharmacokinetic/pharmacodynamic (PK/PD) relationship after intravenous administration of YM758 to tachycardia-induced dogs was investigated and described based on the simplified compartment model. The PK of YM758 in dogs did not differ between the nontreated and tachycardia-induced groups. A drug-induced reduction in heart rate (HR) was clearly observed, and the half-life of the duration of the effect (approximately 4.0 h) was longer than that of the plasma concentration of the unchanged drug. The fitting and simulation procedure from the PK/PD relationship between the time profiles for YM758 plasma concentration and HR reduction had an ECe50 value (YM758 concentration in the effective compartment resulting in a 50% decrease of the maximum effect) of 6.0 ng/ml, which did not agree with the results of the in vitro experiment using right atria isolated from guinea pigs (EC30, 70.4 ng/ml). In addition, in the in vitro experiments, YM758 metabolites had a weak inhibitory effect, if any, on the spontaneous beat rate of the right atria from guinea pigs. These data, along with the previous finding that YM758 and its metabolites are eliminated rapidly from rat hearts, indicate that the duration of the pharmacological effect of YM758 (compared with the rapid elimination of the plasma drug concentration) may be the result of strong binding and/or slower dissociation of YM758 in the If channel. Such PK/PD analyses allow the pharmacological profiles of many drugs, especially cardiovascular drugs, to be more readily understood and better predicted during the clinical stages.
Footnotes
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.108.026385.
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ABBREVIATIONS: HR, heart rate; If channel, “funny” If current channel; YM758, (–)-N-{2-[(R)-3-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)piperidino]ethyl}-4-fluorobenzamide; PK, pharmacokinetics; PD, pharmacodynamics; MIC, minimum inhibitory concentration; Cmax, maximum plasma concentration; AUC, area under the curve; ECG, electrocardiogram; YM-344540, deuterium [d4]-labeled YM758 monophosphate; kel, terminal elimination rate constant; t1/2, elimination half-life; AUCinf, area under the curve extrapolated to infinity; CLtot, total body clearance; Vdss, distribution volume at the steady state; SBR, spontaneous beat rate; YM-234903, (3R-1-{2-[(4-fluorobenzoyl)amino]ethyl} piperidine-3-carboxylic acid; YM-252124, 6,7-dimethoxy-2-[(3R)-piperidin-3-ylcarbonyl]-1,2,3,4-tetrahydroisoquinoline; YM-385459, (5R)-5-[(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl]piperidin-2-one; YM-385461, N-(4-fluorobenzoyl)glycine; YM-385462 (chiral relation to YM-385463), 4-fluoro-N-(2-{(3R)-3-[(4-hydroxy-6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl]piperidin-1-yl}ethyl)benzamide; YM-385463 (chiral relation to YM-385462), 4-fluoro-N-(2-{(3R)-3-[(4-hydroxy-6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl]piperidin-1-yl}ethyl)benzamide; YM-388288 (racemate of YM-385462 and YM-385463), 4-fluoro-N-(2-{(3R)-3-[(4-hydroxy-6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H-yl)carbonyl]piperidin-1-yl}ethyl)benzamide; YM-394111, 4-fluoro-N-(2-{(3R)-3-[(6-hydroxy-7-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl]piperidin-1-yl}ethyl)benzamide; YM-394112, 4-fluoro-N-(2-{(3R)-3-[(7-hydroxy-6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl]piperidin-1-yl}ethyl)benzamide; YM-396944, 2-[2-({[(3R)-1-{2-[(4-fluorobenzoyl)amino]ethyl}piperidin-3-yl]carbonyl}amino)ethyl]-4,5-dimethoxybenzoic acid.
- Accepted April 7, 2009.
- Received December 21, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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Relationship between Exposure of (–)-N-{2-[(R)-3-(6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)piperidino]ethyl}-4-fluorobenzamide (YM758), a “Funny” If Current Channel Inhibitor, and Heart Rate Reduction in Tachycardia-Induced Beagle Dogs
