Genotoxicity and carcinogenicity risk assessment of prucalopride, a selective 5-hydroxytryptamine 4 receptor agonist.

Prucalopride, a high affinity, selective serotonin type 4 (5-HT4) receptor agonist, was associated with increased neoplasia incidence (in endocrine tissues and liver) in 2-year rodent bioassays, without evidence of a genotoxic mechanism of action. Proposed mechanisms of action involve prolactin and the constitutive androstane receptor (CAR). Epigenetic mechanisms and their relevance to humans are discussed. Data from in vitro and in vivo rodent studies demonstrated that prucalopride-related stimulation of prolactin secretion (via dopamine receptor D2 antagonism at high doses) is a rodent-specific, non-genotoxic mechanism for inducing hyperplasia and neoplasia in prolactin receptor-expressing endocrine tissues. Additional data demonstrated that CAR-mediated liver enzyme induction underlies the observed hepatocellular adenomas and thyroid follicular adenomas in rodents. A 12-month neonatal mouse carcinogenicity study confirmed the lack of a genotoxic mechanism of action. Furthermore, tumors were observed only at very high exposures (200 and 63 fold higher in mice and rats, respectively, than human exposure after a daily therapeutic dose of 2 mg). The studies indicate that non-genotoxic, rodent-specific, epigenetic mechanisms that are considered clinically irrelevant are responsible for the increased incidence of neoplasias associated with very high exposure to prucalopride in rodents, and that prucalopride does not pose a carcinogenic safety risk to humans.

Development and validation of a chiral liquid chromatography method for the determination of MP 3950 enantiomers, a high selective 5-HT4 receptor agonist, in rat plasma and its application to stereoselective pharmacokinetic study.

MP 3950 is an active metabolite of mosapride which exhibits high 5-HT4 receptor agonistic effect. The present paper describes an enantioselective chiral HPLC method for separation and quantification of MP 3950 enantiomers in rat plasma. The plasma samples were prepared by liquid-liquid extraction with ethyl acetate and the baseline chromatographic separation was achieved on a Chiralcel OJ-H column with a mobile phase consisting n-hexane/ethanol/methanol/diethylamine (85:5:10:0.4, v/v/v/v) at the flow rate of 1.0mL/min. The ultraviolet detection was performed at 276nm. The calibration curve was linear in the range from 0.100 to 5.00µg/mL with the lower limit of quantification of 0.100µg/mL for each enantiomer. The intra- and inter-day precisions were not more than 14.7%. The accuracy was from -6.4% to 14.0%. The validated method was successfully applied to chiral inversion and stereoselective pharmacokinetic study in rats after oral administration of MP 3950 racemate. The results indicated that no stereochemical inversion was occurred in rats. And the plasma concentrations and area under plasma concentration-time curve of (S)-MP 3950 were all significantly higher than those of (R)-MP 3950 in both male and female rats, which indicated that the disposition of MP 3950 in rats might be stereoselective.

Pharmacokinetics of single and repeated oral doses prucalopride in healthy Chinese volunteers.

AIM: This study investigated the pharmacokinetics of prucalopride in Chinese healthy volunteers. METHODS: This single-center, open-label study was conducted in 14 healthy males and 14 healthy females, aged 18 - 45 years. Fasted subjects received a single dose of 2 mg prucalopride, and after a 7-day wash-out period, they received the same dose once-daily for 7 days at fasted condition. Serial blood samples were taken at predefined time-points to measure plasma concentrations of prucalopride during the single-dose and multi-dose period. Daily evaluations were made on defecation frequency and stool consistency. Safety assessments were performed throughout the study. RESULTS: After oral administration, prucalopride reached the peak plasma level (Cmax) of 4.92 ± 0.78 ng/ml with a median time to Cmax (tmax) of 2 hours and resulted in an area under concentration-time curve (AUC0-∞) of 89.3 ± 15.82 h×ng/ml. Steady state was attained 3 days after repeated dosing, when Cmax was 8.09 ± 1.21 ng/ml and AUC0-24h was 103.6 ± 14.35 h×ng/ml. Pharmacokinetic profiles were similar between genders except males had a slightly lower exposure level. Marked increase of defecation frequencies and predominance of "watery" or "loose" stools were seen after a single dose. The responses during multi-dose period were less remarkable and returned to baseline in 3 days. CONCLUSION: The pharmacokinetics of prucalopride 2 mg oral dose in Chinese healthy volunteers are similar to those observed in Caucasians. Compared to females, males exhibited a slightly lower exposure of prucalopride but similar changes of bowel habits were observed in both genders suggesting the inter-gender pharmacokinetic differences are not clinically relevant.