Celiprolol double-peak occurrence and gastric motility: Nonlinear mixed effects modeling of bioavailability data obtained in dogs

Abstract

Investigation of the underlying mechanism leading to inter- and intrasubject variations in the plasma concentration-time profiles of drugs (1) can considerably benefit rational drug therapy. The significant effect of gastric emptying on the rate and extent of celiprolol absorption and its role with respect to double-peak formation was demonstrated in the present study. In four dogs racemic celiprolol was dosed perorally in a crossover design during four different phases of the fasted-state gastric cycle and gastric motility was recorded simultaneously using a manometric measurement system. Intravenous doses were also given to obtain disposition and bioavailability parameters. The blood samples were assayed by a stereoselective HPLC method (2). The time to onset of the active phase of the gastric cycle showed an excellent correlation with the time to celiprolol peak concentration. Furthermore, bioavailability was increased when celiprolol was administered during the active phase. Double peaks were observed when the first active phase was relatively short, suggesting that a portion of the drug remained in the stomach until the next active phase. Population pharmacokinetic modeling of the data with a two-compartment open model with two lag times incorporating the motility data confirmed the effect of time to gastric emptying on the variability of the oral pharmacokinetics of celiprolol. The fasted-state motility phases determine the rate and extent of celiprolol absorption and influence the occurrence of double peaks. Peak plasma levels of celiprolol exhibit less variability if lag times, and therefore gastric emptying times, are taken into consideration.

Absorption, Metabolism and Excretion of [14C]Mirabegron (YM178), a Potent and Selective β3-Adrenoceptor Agonist, after Oral Administration to Healthy Male Volunteers

“…For humans, the first peak tended to be the highest, whereas for rats the second peak was the larger peak. Several structurally diverse drugs with adequate lipid solubility, such as celiprolol, pafenolol, acebutolol, cimetidine, danazol, veralipride, and talinolol, generate double or multiple peaks or even plateau-like plasma concentration-time profiles (Voinchet et al, 1981;Plusquellec et al, 1987;Lin, 1991;Charman et al, 1993;Lennernäs and Regårdh, 1993;Lipka et al, 1995;Mostafavi and Foster, 2003;Weitschies et al, 2005). The following mechanisms can cause erratic absorption: enterohepatic circulation, fractionated gastric emptying, and separated "absorption windows" along the intestinal tract (Oberle and Amidon, 1987;Gramatté et al, 1994;Roberts et al, 2002).…”

Modeling of Intestinal Drug Absorption: Roles of Transporters and Metabolic Enzymes (For the Gillette Review Series)

“…Various disease conditions and food intake affect stomach emptying and/or intestinal transit (Welling, 1984). Double peak absorption has been correlated with antral gastric motility (Oberle and Amidon,1987;Plusquellec et al, 1987;Suttle et al, 1992;Langguth et al, 1994;Lipka et al, 1995;Suttle and Brouwer, 1995;Wang et al, 1999;Takamatsu et al, 2002;Kimura and Higaki, 2002;Yin et al, 2003) as well as other factors including the presence of adjuvants (Basit et al, 2002) or bile salts (Lennernäs and Regardh, 1993). The data showing double peaks during absorption have been modeled as the discontinuous oral absorption model (Witcher and Boudinot, 1996).…”

Issues Related to the Use of Canines in Toxicologic Pathology—Issues With Pharmacokinetics and Metabolism

“…Comparisons of fasted dogs and humans have shown significant similarity in the patterns of gastric contractions (Table 2) (18). An interesting example of the importance of gastric motility is seen in a study by Lipka et al (39) examining the absorption of celiprolol. Oral doses of celiprolol were administered to fasted dogs fitted with monitors of gastric motor activity.…”