Abstract
In the present study the pharmacokinetics and pharmacodynamics of tamsulosin were investigated in anesthetized male dogs. Hypogastric nerve stimulation elevated the intraurethral pressure (IUP), which was inhibited dose dependently by intraduodenal administration of tamsulosin (3–30 μg/kg). The inhibition peaked about 90 min after dosing and lasted up to 240 min. The basal mean blood pressure did not change significantly during the observation period. The plasma, prostatic, and urethral concentrations of tamsulosin were determined by the liquid chromatography-mass spectrometry/mass spectrometry method. The plasma concentration reached the maximal level within 30 min after dosing and gradually declined thereafter. The maximal total plasma concentration of tamsulosin (Cmax, t) and its unbound concentration (Cmax, u) correlated with the maximal effect on IUP response [r2 = 0.81 (p < 0.01, n = 15) andr2 = 0.84 (p < 0.01, n = 15), respectively]. Each individual unbound plasma concentration did not correlate, however, with its associated inhibition of IUP response (r2 = 0.04, n = 126). Although the plasma concentration of tamsulosin decreased nearly to the lower limit of quantitation 240 min after dosing, the prostatic and urethral concentrations remained high, i.e., 13 to 44 times greater than the plasma concentration. Our data demonstrate that the maximal inhibition by tamsulosin of IUP response is well correlated with the maximal plasma concentration in the early phase. The sustained effect of tamsulosin on IUP response that follows may be related to prostatic and urethral retention of tamsulosin.
Footnotes
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Send reprint requests to: Dr. Shuichi Sato, Applied Pharmacology Research, Pharmacology Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., 21, Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan. E-mail:sato{at}yamanouchi.co.jp
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↵1 Present address: Drug Metabolism Laboratories Institute for Drug Development Research, Yamanouchi Pharmaceutical Co., Ltd., 3-17-1, Hasune, Itabashi-Ku, Tokyo 174-8612, Japan.
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↵2 Present address: Safety Research Laboratories, Institute for Drug Development Research, Yamanouchi Pharmaceutical Co., Ltd., 1-1-8, Azusawa, Itabashi-Ku, Tokyo 174-8511, Japan.
- Abbreviations:
- LUTS
- lower urinary tract symptoms
- HNS
- hypogastric nerve stimulation
- IUP
- intraurethral pressure
- LLOQ
- lower limit of quantitation
- Ct
- total plasma concentration
- Cu
- unbound plasma concentration
- fu
- fraction of unbound drug in plasma
- Cmax, t
- maximal total plasma concentration
- Cmax, u
- maximal unbound plasma concentration
- Tmax
- time to reach maximal plasma concentration
- AUClast, t
- area under the total plasma concentration-time curve up to the last measurable time point
- AUClast, u
- area under the unbound plasma concentration-time curve up to the last measurable time point
- MBP
- mean blood pressure
- i.d.
- intraduodenal
- Emax
- maximal effect
- Received June 21, 2000.
- Accepted November 23, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
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