Evaluation of beagle dogs as an animal model for bioavailability testing of cinnarizine capsules

Ogata, Hiroyasu; Aoyagi, Nobuo; Kaniwa, Nahoko; Ejima, Akira; Kitaura, Toshiyuki; Ohki, Toshimitsu; Kitamura, Koichi

doi:10.1016/0378-5173(86)90109-2

Cited by 20 publications

(6 citation statements)

References 14 publications

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“…Cynomolgus monkeys offer the following advantages over beagle dogs as an animal model. It has been reported that the gastric pH, which can affect the dissolution of drugs from pharmaceutical products and therefore their bioavailability, of unfed monkeys is similar to the gastric pH of fasting humans [28]; in contrast, the gastric pH of beagle dogs is highly variable both within and between subjects [29,30]. Additionally, the rate and the extent of drug absorption in monkeys are more similar to humans than those in dogs [31,32].…”

Section: Oro-caecal Transit Time Of Liquids In Unfed Cynomolgus Monkeysmentioning

confidence: 99%

Gastrointestinal transit of liquids in unfed cynomolgus monkeys

Kondo¹,

Takahashi²,

Watanabe³

et al. 2003

Biopharm & Drug Disp

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In this study, the gastric emptying rate and oro-caecal transit time of two liquid volumes (20 and 60 ml) were compared in unfed cynomolgus monkeys. First, the acetaminophen method was used to determine the gastric half-emptying time (t(50%)). The mean t(50%) from seven monkeys was 21.2 min for the 20-ml volume and 27.8 min for the 60-ml volume. This mean t(50%) in monkeys is similar to that reported previously in fasting humans. Next, the sulfasalazine-sulfapyridine method was used to determine median oro-caecal transit times for the 2 liquid volumes; these times were 2.5 h for the 20-ml volume and 2.3 h for the 60-ml volume, which are about 1.5 h shorter than previously reported transit times in humans. An increase in volume administered did not significantly change either the t(50%) or oro-caecal transit time. The data also show that variability in both t(50%) and oro-caecal transit time within each monkey is not as great as the large variability between monkeys. Consequently, cynomolgus monkeys are good model animals to use for studies on the gastric emptying of drug-containing liquids after fasting; however, analysis of results from bioavailability studies must compensate for differences in the oro-caecal transit time between monkeys and humans.

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Section: Oro-caecal Transit Time Of Liquids In Unfed Cynomolgus Monkeysmentioning

confidence: 99%

Gastrointestinal transit of liquids in unfed cynomolgus monkeys

Kondo¹,

Takahashi²,

Watanabe³

et al. 2003

Biopharm & Drug Disp

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“…In contrast, after having a meal, the gastric pH of a healthy person temporarily shifts from the acid range towards a more neutral range, and returns to the acid range within a brief period [9,10]. In contrast, the gastric pHs of unfed beagle dogs, which are popular model animals, are highly variable both within and among subjects, and show extreme variability both within and among measurements [11,12]. Thus, there is a significant difference between the variability of the human gastric pH profiles, which are relatively uniform, and the beagle dog profiles, which are highly variable.…”

Section: Introductionmentioning

confidence: 99%

Characteristics of the gastric pH profiles of unfed and fed cynomolgus monkeys as pharmaceutical product development subjects

Kondo¹,

Shinoda²,

Nakashima³

et al. 2002

Biopharm & Drug Disp

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Gastric pH is an important factor which significantly affects the dissolution of drugs, and therefore their bioavailability. In this study, the gastric pHs were measured directly with a miniature pH electrode inserted through the nostril into the body of the stomach of cynomolgus monkeys. Results from three separate sets of measurements using the same male monkeys indicated that the median gastric pH profiles of unfed monkeys were low, fluctuating between pH 1 and pH 3. However, the median gastric pHs in fed monkeys given about 108 g of a biscuit-type solid food, which are commonly provided, shifted toward a more neutral range between pH 5 and pH 7, and remained in this range for about 9 h. This result contrasted with reported results for humans after eating a standard meal, which showed a neutral range between pH 5 and pH 7 for a brief period. Consequently, these results indicate that although the gastric pH of unfed cynomolgus monkeys is similar to that of fasting humans, there is a great difference in the gastric pH profiles between humans and monkeys after eating, which suggests that further studies are needed to establish optimal feeding conditions for bioavailability studies in monkeys.

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“…The N-phosphonooxymethyl prodrugs of two drugs, cinnarizine [3][4][5][6][7] and loxapine, 8 were selected for the in vivo evaluation of this prodrug strategy. Both drugs are sparingly water soluble.…”

Section: Introductionmentioning

confidence: 99%

A novel prodrug approach for tertiary amines. 3. In vivo evaluation of two N‐phosphonooxymethyl prodrugs in rats and dogs

Krise¹,

Charman²,

Charman³

et al. 1999

Journal of Pharmaceutical Sciences

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N-phosphonooxymethyl derivatives of tertiary amine containing drugs have been identified as a novel prodrug approach for improving aqueous solubility. The in vivo reversion of two prodrugs to the corresponding parent compounds following iv and im administration to rats and dogs was investigated. Equimolar doses of parent drugs (loxapine or cinnarizine) and the corresponding prodrugs were each administered via a rapid iv infusion to rats and dogs. Equimolar doses of loxapine and its prodrug were each administered im to rats only. Blood samples were collected over 12 h, and plasma was assayed for both parent drug and intact prodrug by HPLC. Comparison of the plasma AUC for the parent drugs following administration of the parent drugs and prodrugs allowed estimation of the apparent bioavailability of parent drug from prodrug dosing. Plasma levels of the prodrugs fell below the limit of detection 5 min after iv infusion with an approximate half-life of 1 min. The mean AUCs following iv and im dosing of parent drugs were not statistically different from the parent drug AUCs obtained after prodrug dosing. The results are consistent with rapid and quantitative prodrug to parent drug reversion following administration of the phosphonooxymethyl prodrugs to the rats and dogs. This information, together with previous studies on the synthesis and physicochemical evaluation of the prodrugs, suggests that this novel prodrug strategy is a very promising approach for overcoming solubility limitations seen with many tertiary amine containing drugs at physiological pH values.

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Evaluation of beagle dogs as an animal model for bioavailability testing of cinnarizine capsules

Cited by 20 publications

References 14 publications

Gastrointestinal transit of liquids in unfed cynomolgus monkeys

Gastrointestinal transit of liquids in unfed cynomolgus monkeys

Characteristics of the gastric pH profiles of unfed and fed cynomolgus monkeys as pharmaceutical product development subjects

A novel prodrug approach for tertiary amines. 3. In vivo evaluation of two N‐phosphonooxymethyl prodrugs in rats and dogs

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