Different Absorption Profiles of Deramciclane in Man and in Dog

Abstract

We have studied the dog model for predicting the oral absorption of deramciclane, a novel anxiolytic compound, as a model acid-labile drug. The absorption profile of deramciclane was studied in man and beagle dogs after administration of conventional capsules and enteric coated tablets. Absorption in dogs pretreated with pentagastrin or saline was also studied after administration of conventional capsules. The in-vitro stability of deramciclane was determined over the pH range 1.2-6.0. The rate of degradation of deramciclane increased ten-fold as the pH was reduced from 2.1 to 1.2 (t 1/2 beta (elimination half-life) 9 h and 39 min, respectively). Deramciclane was stable at pH > or = 3. The two formulations were bioequivalent in dogs and there were no significant differences between pharmacokinetic parameters measured for dogs pretreated with pentagastrin or saline. In man the mean relative bioavailability and Cmax (peak plasma concentration) for the conventional capsules were approximately 75% and 83% of those for the enteric coated tablets (P = 0.0004 and P = 0.0031, respectively). This was probably because of degradation of deramciclane at lower pH of man's stomach compared with that of the dog. Pentagastrin was probably unsuccessful in reducing gastric pH and thus no change in absorption was observed. It is concluded that the absorption of deramciclane, and possibly other acid-labile drugs, cannot be predicted by use of the dog model.

Development of a Canine Model to Enable the Preclinical Assessment of Ph-dependent Absorption of Test Compounds

“…Beagle dogs have frequently been used as a surrogate to human for the study of drug absorption because of their ability to ingest human‐scale dosage forms and their ease of handling. However, significant differences exist between the oral bioavailability observed in dogs and that observed in humans 16,17. Gastric pH in humans has been evaluated using a variety of methodologies, including orogastric or nasogastric intubation and aspiration, direct measurement via a pH probe in the stomach, and radiotelemetry (e.g., Heidelberg capsule).…”

“…However, significant differences exist between the oral bioavailability observed in dogs and that observed in humans. 16,17 Gastric pH in humans has been evaluated using a variety of methodologies, including orogastric or nasogastric intubation and aspiration, direct measurement via a pH probe in the stomach, and radiotelemetry (e.g., Heidelberg capsule). Regardless of the method used, fasting gastric pH in humans has been reported to be less than 3.…”

Pharmacokinetics of SB‐247083, a potent and selective endothelinA receptor antagonist, in the rat, dog, and monkey

“…Formulation 5: Formulation 4 administered to dogs that were pre-treated orally with 4 ml/kg 0.1 N HCl. * = Significantly different from all other treatment groups, p50.01, one-way ANOVA with Bonferroni multiple comparisons post-test co-workers [18]. To avoid the ambiguity of this indirect approach in the present investigation, the pH of the fasted dog stomach was manipulated directly.…”

“…To attempt to normalize the pH of the fasted dog stomach to that of other preclinical species and of human, various investigators have attempted to artificially decrease the dog stomach pH. Knupp and colleagues [17] successfully pretreated dogs with pentagastrin to stimulate HCl release, while the same technique proved variable and unsuccessful in a study by Kanerva and co-workers [18]. To avoid the ambiguity of this indirect approach in the present investigation, the pH of the fasted dog stomach was manipulated directly.…”

Synthesis of deramciclane* labeled with tritium in various positions

“…[2][3][4] Previously published pharmacokinetic studies in several different species, including man, have shown extensive metabolism, with cleavage of the side chain the major metabolic pathway. [5][6][7][8][9][10] The resulting metabolite and derivatives show increased distribution and significant plasma levels for a longer biological half-life than the parent compound. 11,12 Two tritium labelled forms of deramciclane were required with the label in the camphor skeleton, ([3-3 H]deramciclane (3)) and the side chain ([2-dimethylamino-[2-3 H]ethoxy]deramciclane (9)) for in vitro and in vivo studies to further investigate various aspects of the metabolism and pharmacokinetics of deramciclane.…”