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ABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Blood-Brain Barrier Permeability of Novel [D-Arg²]Dermorphin (1-4) Analogs: Transport Property Is Related to the Slow Onset of Antinociceptive Activity in the Central Nervous System

Department of Drug Disposition and Pharmacokinetics, School of Pharmaceutical Sciences, Teikyo University, Kanagawa, Japan (Y.D.); Department of Biopharmaceutics, Hokkaido College of Pharmacy, Hokkaido, Japan (Y.N., Y.M., K.M.); New Industry Creation Hatchery Center and Department of Molecular Biopharmacy and Genetics, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan (S.O., T.T.); Department of Physiology and Anatomy, Tohoku Pharmaceutical University, Sendai, Japan (S.S.); Faculty of Pharmaceutical Sciences, Toyama Medical and Pharmaceutical University, Toyama, Japan (K.H.); and CREST of Japan Science and Technology Agency, Hokkaido, Japan (S.O., K.H., T.T.)

To clarify the pharmacological characteristics of N-amidino-Tyr-D-Arg-Phe-Ala-OH (ADAB) and N-amidino-Tyr-D-Arg-Phe-MeAla-OH (ADAMB), µ₁-opioid receptor-selective [D-Arg²]dermorphin tetrapeptide analogs, the plasma pharmacokinetics, and the in vivo blood-brain barrier (BBB) transport of these peptides were quantitatively evaluated. The mechanism responsible for the BBB transport of these peptides was also examined. The in vivo BBB permeation influx rates of ¹²⁵I-ADAB and ¹²⁵I-ADAMB after an i.v. bolus injection into mice were determined to be 0.0515 ± 0.0284 µl/(min · g of brain) and 0.0290 ± 0.0059 µl/(min · g of brain), respectively, both rates being slower than that of ¹²⁵I-Tyr-D-Arg-Phe-Ala-OH (¹²⁵I-TAPA), a [D-Arg²]dermorphin tetrapeptide analog. To elucidate the BBB transport mechanism of ADAB and ADAMB, a conditionally immortalized mouse brain capillary endothelial cell line (TM-BBB4) was used as an in vitro model of the BBB. The internalization of both ¹²⁵I-ADAB and ¹²⁵I-ADAMB into cells was concentration-dependent with half-saturation constant (K_d) values of 3.76 ± 0.83 and 5.68 ± 1.75 M, respectively. µ The acid-resistant binding of both ADAB and ADAMB was significantly inhibited by dansylcadaverine (an endocytosis inhibitor) and poly-L-lysine and protamine (polycations), but it was not inhibited by 2,4-dinitrophenol, or at 4°C. These results suggest that ADAB and ADAMB are transported through the BBB with slower permeation rates than that of TAPA, and this is likely to be a factor in the slow onset of their antinociceptive activity in the central nervous system. The mechanism of the BBB transport of these drugs is considered to be adsorptive-mediated endocytosis.

Address correspondence to: Dr. Yoshiharu Deguchi, Department of Drug Disposition and Pharmacokinetics, School of Pharmaceutical Sciences, Teikyo University, 1091-1 Suarashi, Sagamiko-machi, Tsukui-gun, Kanagawa 199-0195, Japan. E-mail: deguchi{at}pharm.teikyo-u.ac.jp