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Drug Metabolism and Disposition Fast Forward
First published on July 20, 2005; DOI: 10.1124/dmd.104.001040

0090-9556/05/3310-1488-1494$20.00
DMD 33:1488-1494, 2005

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PHYSIOLOGICALLY BASED PHARMACOKINETIC MODEL FOR PRALMORELIN HYDROCHLORIDE IN RATS

Risa Nasu, Yoichi Kumagai, Hirokuni Kogetsu, Masayuki Tsujimoto, Hisakazu Ohtani1, and Yasufumi Sawada1

Pharmacokinetics Department, Central Research Laboratories, Kaken Pharmaceutical Co., Ltd., Shizuoka, Japan (R.N., Y.K., H.K.); and Department of Medico-Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan (M.T., H.O., Y.S.)

Pralmorelin hydrochloride (pralmorelin), consisting of six amino acid residues, is a growth hormone-releasing peptide. The aim of this study is to analyze the pharmacokinetics of pralmorelin after intravenous bolus administration to rats, and to develop a physiologically based pharmacokinetic (PB-PK) model to describe and predict the concentrations of pralmorelin in blood and tissues. Pralmorelin (3 mg/kg) was administered intravenously to 24 Sprague-Dawley rats. Groups of three rats were sacrificed by decapitation at each designated time point (up to 4 h), and plasma and tissues (brain, lung, heart, liver, kidney, small intestine, muscle, adipose, and skin) were collected. Bile was also pooled until decapitation. The concentration of pralmorelin in samples was determined by liquid chromatography-tandem mass spectrometry. Plasma concentrations of pralmorelin declined rapidly in a biexponential manner. Biliary excretion of pralmorelin was so rapid that 80% of the dose was recovered unchanged in the bile within 1 h after administration. The distribution parameters in each tissue were obtained by using a hybrid model and an integration plot. They revealed that the distribution of pralmorelin into liver was blood flow-limited, and its distribution was permeability-limited in all other tissues. The PB-PK model developed in this study well described the time courses of pralmorelin concentration in the blood and tissues of rats.

Address correspondence to: Prof. Yasufumi Sawada, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 3-14-15 Hongo, Tokyo 113-0033, Japan. E-mail: sawada{at}mol.f.u-tokyo.ac.jp






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