Evaluation of in vivo dissolution behavior and GI transit of griseofulvin, a BCS class II drug.
Mean plasma concentration-time profile of griseofulvin, a BCS class II drug, orally administered as powders into rats, was predicted based on GITA model. However, it was very difficult to predict the individual plasma profile because of large inter-individual difference. As the absorption of griseofulvin would be rate-limited by the dissolution process, we tried to analyze the in vivo dissolution kinetics of griseofulvin by focusing on gastric emptying and intestinal transit as physiological factors influencing the in vivo dissolution kinetics. After oral administration of griseofulvin, theophylline and sulfasalazine into rats, gastric emptying and intestinal transit were simultaneously estimated by analyzing the absorption kinetics of theophylline and observing the appearance of sulfapyridine in plasma, respectively. Gastric emptying kinetics was not significantly correlated with absorption or dissolution behavior of griseofulvin. On the other hand, the cecum-arriving time reflecting the intestinal transit was significantly correlated with both AUC and total dissolved amount of griseofulvin. T(max) of griseofulvin also increased with the increase of cecum-arriving time. These results clearly indicate that the longer residence time could lead to the higher dissolution and absorption of griseofulvin and that the variance of intestinal transit could be responsible for the inter-individual difference of the in vivo absorption behavior.
Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Okayama University, 1-1-1 Tsushima-naka, Okayama 700-8530, Japan.
Yoshitsugu
Y
Fujioka
Yukiko
Y
Metsugi
Ken-Ichi
K
Ogawara
Kazutaka
K
Higaki
Toshikiro
T
Kimura
D000284:Administration, Oral; D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D002432:Cecum / Q000378:metabolism; D005746:Gastric Emptying; D005772:Gastrointestinal Transit; D006118:Griseofulvin / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D007275:Injections, Intravenous; D007408:Intestinal Absorption; D008297:Male; D008954:Models, Biological; D011208:Powders; D051381:Rats; D017208:Rats, Wistar; D012995:Solubility; D013427:Sulfapyridine / Q000493:pharmacokinetics; D013806:Theophylline / Q000493:pharmacokinetics
D000935:Antifungal Agents; D011208:Powders; D006118:Griseofulvin; D013806:Theophylline; D013427:Sulfapyridine