S-carvedilol(AHN-GOOK PHARMACEUTICAL Co., Ltd.)

Roux‐en‐Y gastric bypass is one of the most common surgical treatments for obesity due to the effective long‐term weight loss and remission of associated comorbidities. Carvedilol, a third‐generation β‐blocker, is prescribed to treat cardiovascular diseases. This drug is a weak base with low and pH‐dependent solubility and dissolution and high permeability. As the changes in the gastrointestinal tract anatomy and physiology after roux‐en‐Y gastric bypass can potentially affect drug pharmacokinetics, this study aimed to assess the effect of roux‐en‐Y gastric bypass on the pharmacokinetics of carvedilol enantiomers. Nonobese (n = 15, body mass index < 25 kg/m2), obese (n = 19, body mass index ≥ 30), and post‐roux‐en‐Y gastric bypass subjects submitted to surgery for at least 6 months (n = 19) were investigated. All subjects were administered a single oral dose of 25‐mg racemic carvedilol, and blood was sampled for up to 24 hours. Plasma concentrations of (R)‐ and (S)‐carvedilol were determined by liquid chromatography–tandem mass spectrometry. The maximum plasma concentration (Cmax) and the area under the plasma concentration‐time curve (AUC) of (R)‐carvedilol were 2‐ to 3‐fold higher than (S)‐carvedilol in all groups. Obese subjects have shown reduced Cmax of (R)‐ and (S)‐carvedilol without changing the AUC. Post‐roux‐en‐Y gastric bypass subjects presented a 3.5‐fold reduction in the Cmax of the active (S)‐carvedilol and a 1.9 reduction in the AUC from time 0 to infinity compared to nonobese subjects. The time to reach Cmax of (S)‐carvedilol increased 2.5‐fold in post‐roux‐en‐Y gastric bypass subjects compared to obese or nonobese. Although the β‐blockade response was not assessed, the reduced exposure to carvedilol in subjects post‐roux‐en‐Y gastric bypass may be clinically relevant and require dose adjustment.

Skin cancer is the most common malignancy worldwide and is rapidly rising in incidence, representing a significant public health challenge. The β-blocker, carvedilol, has shown promising effects in preventing skin cancer. However, as a potent β-blocker, repurposing carvedilol to an anticancer agent is limited by cardiovascular effects. Carvedilol is a racemic mixture consisting of equimolar S- and R-carvedilol, whereas the R-carvedilol enantiomer does not possess β-blocking activity. Because previous studies suggest that carvedilol's cancer preventive activity is independent of β-blockade, we examined the skin cancer preventive activity of R-carvedilol compared with S-carvedilol and the racemic carvedilol. R- and S-carvedilol were equally effective in preventing EGF-induced neoplastic transformation of the mouse epidermal JB6 Cl 41-5a (JB6 P+) cells and displayed similar attenuation of EGF-induced ELK-1 activity. R-carvedilol appeared slightly better than S-carvedilol against UV-induced intracellular oxidative stress and release of prostaglandin E2 from the JB6 P+ cells. In an acute UV-induced skin damage and inflammation mouse model using a single irradiation of 300 mJ/cm2 UV, topical treatment with R-carvedilol dose dependently attenuated skin edema and reduced epidermal thickening, Ki-67 staining, COX-2 protein, and IL6 and IL1β mRNA levels similar to carvedilol. In a chronic UV (50–150 mJ/cm2) induced skin carcinogenesis model in mice with pretreatment of test agents, topical treatment with R-carvedilol, but not racemic carvedilol, significantly delayed and reduced skin squamous cell carcinoma development. Therefore, as an enantiomer present in an FDA-approved agent, R-carvedilol may be a better option for developing a safer and more effective preventive agent for skin carcinogenesis.

In this study, we demonstrated the skin cancer preventive activity of R-carvedilol, the non-β-blocking enantiomer present in the racemic β-blocker, carvedilol. As R-carvedilol does not have β-blocking activity, such a preventive treatment would not lead to common cardiovascular side effects of β-blockers.