Intrinsic absolute bioavailability prediction in rats based on in situ absorption rate constants and/or in vitro partition coefficients: 6-fluoroquinolones.
A preliminary study attempting to predict the intrinsic absolute bioavailability of a group of antibacterial 6-fluoroquinolones-including true and imperfect homologues as well as heterologues-was carried out. The intrinsic absolute bioavailability of the test compounds, F, was assessed on permanently cannulated conscious rats by comparing the trapezoidal normalized areas under the plasma concentration-time curves obtained by intravenous and oral routes (n = 8-12). The high-performance liquid chromatography analytical methods used for plasma samples are described. Prediction of the absolute bioavailability of the compounds was based on their intrinsic rat gut in situ absorption rate constant, k(a). The working equation was: where T represents the mean absorbing time. A T value of 0.93 (+/-0.06) h provides the best correlation between predicted and experimentally obtained bioavailabilities (F' and F, respectively) when k(a) values are used (slope a = 1.10; intercept b = -0.05; r = 0.991). The k(a) values can also be expressed in function of the in vitro partition coefficients, P, between n-octanol and a phosphate buffer. In this case, theoretical k(a) values can be determined with the parameters of a standard k(a)/P correlation previously established for a group of model compounds. When P values are taken instead of k(a) values, reliable bioavailability predictions can also be made. These and other relevant features of the method are discussed.
Sánchez-Castaño
G
G
Department of Pharmaceutics, Faculty of Pharmacy, University of Valencia, Av. Vicente Andrés Estellés s/n. 46100-Valencia, Spain.
Ruíz-García
A
A
Bañón
N
N
Bermejo
M
M
Merino
V
V
Freixas
J
J
Garriguesx
T M
TM
Plá-Delfina
J M
JM
D000042:Absorption / Q000502:physiology; D000818:Animals; D000890:Anti-Infective Agents / Q000097:blood* / Q000493:pharmacokinetics; D019540:Area Under Curve; D001682:Biological Availability; D004064:Digestive System / Q000378:metabolism; D024841:Fluoroquinolones; D008297:Male; D051381:Rats; D017208:Rats, Wistar
D000890:Anti-Infective Agents; D024841:Fluoroquinolones