Studies on alkyl-xanthine derivatives. II. Pharmacokinetic and pharmacodynamic studies of a new bronchodilator, 1-methyl-3-propylxanthine (MPX).
A new xanthine derivative bronchodilator, 1-methyl-3-propylxanthine (MPX), and 1-methyl-3-butylxanthine (MBX) were synthesized. We evaluated their relaxant effects on tracheal smooth muscle isolated from guinea pigs and pharmacokinetic characteristics in rats using 1,3-dimethylxanthine (theophylline, TPH) as the reference drug. Dose-dependent relaxant effects were observed in the concentration range of 1 x 10(-6) to 1 x 10(-4) M, and both MPX and MBX exert very much stronger relaxant effects than TPH with nearly equal potency. There were significant differences in the pharmacokinetic and physico-chemical properties among these drugs, both MPX and MBX having shorter half-lives, higher plasma protein binding in vivo and stronger hydrophobicity compared to TPH. The present study suggested that the N3-alkyl chain length is significant for increasing the relaxant effect and affecting the pharmacokinetic and physico-chemical properties of these drugs.
Ruttikorn
A
A
Department of Hospital Pharmacy, Nagoya University School of Medicine, Japan.
Takagi
K
K
Nadai
M
M
Kuzuya
T
T
Ogawa
K
K
Miyamoto
K
K
Hasegawa
T
T
D000818:Animals; D001993:Bronchodilator Agents / Q000493:pharmacokinetics* / Q000494:pharmacology; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship; D013806:Theophylline / Q000493:pharmacokinetics / Q000494:pharmacology; D014132:Trachea / Q000187:drug effects; D014970:Xanthines / Q000493:pharmacokinetics* / Q000494:pharmacology
D001993:Bronchodilator Agents; D014970:Xanthines; C058490:1-methyl-3-butylxanthine; C058491:1-methyl-3-propylxanthine; D013806:Theophylline