Nonlinear intestinal pharmacokinetics of mitemcinal, the first acid-resistant non-peptide motilin receptor agonist, in rats.
The objective was to investigate the mechanism of nonlinear pharmacokinetics of mitemcinal, the first acid-resistant non-peptide motilin agonist, in rats. Super-proportional increases of the cumulative rates of radioactivity excreted into bile and urine following oral administration of [3H]-mitemcinal suggested nonlinear absorption of mitemcinal in rats. To evaluate the fraction dose absorbed (Fa) and intestinal availability (Fg), [3H]-mitemcinal was orally administrated to rats, and tritium radioactivity and unchanged mitemcinal concentration were determined in the portal blood. Fa values for 0.2 mg/kg1, 0.5 mg/kg, and 5.0 mg/kg dose groups were 0.314, 0.353, and 0.569, respectively. Corresponding Fg values were 0.243, 0.296, and 0.513, respectively. In Caco-2 experiments, the permeation of [3H]-mitemcinal in the secretory direction was larger than in the absorptive direction and was inhibited by P-glycoprotein (P-gp) substrate digoxin. The results indicate that the saturation of P-gp-mediated membrane permeation and intestinal metabolism causes the nonlinear pharmacokinetics of mitemcinal in rats.
Saitoh
Ryoichi
R
Pre-clinical Research Department, Chugai Pharmaceutical Co, Ltd., Japan. saitorui@chugai-pharm.co.jp
Miyayama
Takashi
T
Mitsui
Tetsuya
T
Akiba
Yuko
Y
Higashida
Atsuko
A
Takata
Shotaro
S
Kawanishi
Takehiko
T
Aso
Yoshinori
Y
Itoh
Zen
Z
Omura
Satoshi
S
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors; D000284:Administration, Oral; D000818:Animals; D001646:Bile / Q000378:metabolism; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability / Q000187:drug effects; D004077:Digoxin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004917:Erythromycin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D006801:Humans; D007408:Intestinal Absorption / Q000187:drug effects; D007413:Intestinal Mucosa / Q000378:metabolism*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D011964:Receptors, Gastrointestinal Hormone / Q000037:antagonists & inhibitors*; D018013:Receptors, Neuropeptide / Q000037:antagonists & inhibitors*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D011964:Receptors, Gastrointestinal Hormone; D018013:Receptors, Neuropeptide; C050802:motilin receptor; D004917:Erythromycin; C103741:mitemcinal; D004077:Digoxin