Application of Gastric Acidity-Controlled Beagle Dog to Bioavailability Study of Cinnarizine

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Abstract
The relationship between gastric acidity and bioavailability of a weakly basic drug, cinnarizine (CN) was investigated in the gastric acidity-controlled beagle dogs. The dissolution of CN from capsules was very fast at pH 1.2 but it decreased with an increase in pH. The capsules containing CN were orally administered to the beagle dogs of the following three groups: 1) the dogs whose gastric acidity were not controlled; 2) the dogs whose gastric acidity were controlled to high levels (less than pH 2) with pentagastrin; 3) the dogs whose gastric acidity were controlled to low levels (more than pH 6) with omeprazole. The peak plasma concentration (Cmax) and the area under the plasma concentration-time curve (AUC0-8h) of CN were most variable in the first group. On the other hand, the variations of these parameters were small in the second and third groups. The Cmax and AUC0-8h of CN in the high acidity group were about 20 times larger than those in the low acidity group (p < 0.01). The bioavailability of CN was markedly influenced by the gastric acidity. This finding was similiar to that in human subjects. The gastric acidity-controlled beagle dogs are useful animal models of evaluate the bioavailability of weakly basic drugs such as CN, exhibiting pH-dependent dissolution behavior.