The effect of solubilization on the oral bioavailability of three benzimidazole carbamate drugs.
The effect of solubilization by complexation with povidone on the oral bioavailability of three anthelmintic benzimidazole carbamate drugs: mebendazole (MBZ), albendazole (ABZ) and ricobendazole (RBZ), was studied in mice. The following in vitro characteristics of the initial raw materials and the drug-povidone complexes were evaluated: melting point (MP); mean dissolution time (MDT); solubility constants (Cs) in n-octanol, acid (pH 1.2) and neutral (pH 7.4) aqueous media; apparent partition coefficients (P) and capacity factors (k'W) determined by HPLC. The following in vivo parameters were also evaluated: AUC(0-infinity), C(max), T(max) and MRT. The possible relationship between in vitro characteristics and in vivo parameters was explored and it was found that an increase in solubility, especially in acidic medium, leads to an increase in AUC and C(max) and a decrease in T(max). Therefore, dissolution seems to be the absorption limiting step for these drugs. For the in vivo parameters related to the amount of absorbed drug (AUC and C(max)), the best correlation was obtained with the in vitro characteristics related to solubility which are Cs, MP and MDT. On the other hand, there were good linear correlations between T(max) which is an in vivo parameter related to the rate of drug absorption, and the lipophilia/hydrophilia (logP and log k'W) relation-parameters.
Daniel-Mwambete
K
K
Departamento de Parasitología, Facultad de Farmacia, Universidad Complutense de Madrid, Plaza Ramón y Cajal, 28040 Madrid, Spain.
Torrado
Susana
S
Cuesta-Bandera
C
C
Ponce-Gordo
F
F
Torrado
J J
JJ
D000277:Adjuvants, Pharmaceutic / Q000737:chemistry; D000284:Administration, Oral; D015766:Albendazole / Q000031:analogs & derivatives* / Q000097:blood / Q000737:chemistry* / Q000493:pharmacokinetics; D000818:Animals; D000871:Anthelmintics / Q000097:blood / Q000737:chemistry* / Q000493:pharmacokinetics; D019540:Area Under Curve; D001682:Biological Availability; D002626:Chemistry, Pharmaceutical; D002851:Chromatography, High Pressure Liquid; D016014:Linear Models; D008463:Mebendazole / Q000097:blood / Q000737:chemistry* / Q000493:pharmacokinetics; D051379:Mice; D011205:Povidone / Q000737:chemistry; D012995:Solubility; D013997:Time Factors
D000277:Adjuvants, Pharmaceutic; D000871:Anthelmintics; D008463:Mebendazole; D015766:Albendazole; D011205:Povidone; C027186:albendazole sulfoxide