Sustained Increase in the Oral Bioavailability of Loperamide after a Single Oral Dose of HM30181, a P‐glycoprotein Inhibitor, in Healthy Male Participants

Abstract

HM30181 is a new P-glycoprotein (P-gp) inhibitor. This study was conducted to investigate the effect of HM30181 and its duration of action on P-gp inhibition using loperamide as a probe drug. An open-label, five-period, fixed-sequence, cross-over study was conducted in 25 healthy Korean participants, who received a single oral dose of loperamide at 16 mg in five periods lasting for 17 days. In period II, participants also randomly received a single oral dose of HM30181 at 1, 5, 10, 15 mg simultaneously with loperamide. Serial pharmacokinetic blood samples were obtained up to 72 and 336 hr after loperamide and HM30181 administration, respectively. A mixed-effects analysis was performed to compare the area under the plasma concentration versus time curve from time 0 to 72 hr (AUC0-72 hr ) between periods and HM30181 dose groups. Tolerability was also assessed. The AUC0-72 hr of repeatedly administered loperamide was significantly increased 1.18-1.62 times for up to 14 days after a single oral administration of HM30181, particularly at doses ≥10 mg although the between-group difference failed to reach statistical significance. Plasma HM30181 was not detected in many participants including none at any sampling points beyond 48 hr after administration. Most adverse events (AEs) were mild to moderate and resolved spontaneously. The oral bioavailability of loperamide was significantly enhanced by a single oral administration of HM30181, which was sustained for up to 14 days. HM30181 was well tolerated in this selected population.

Effects of HM30181, a P‐glycoprotein inhibitor, on the pharmacokinetics and pharmacodynamics of loperamide in healthy volunteers

“…1 g in 4556 l, at pH 3.8) [7], the P-gp Effects of HM30181, a P-glycoprotein inhibitor inhibitory action of HM30181 could be local, i.e. in the gut lumen, which was also suggested in a previous study [24]. Collectively, the moderate inhibition of P-gp by HM30181, thought to be primarily in the intestine, may be construed as beneficial because it enables more specific P-gp inhibition, leading to fewer adverse events.…”

Measurement of Rhodamine 123 in Three‐Dimensional Organoids: A Novel Model for P‐Glycoprotein Inhibitor Screening

“…P‐gp, belonging to the family of ATP‐binding cassette (ABC) transporters, is localized at the apical side of the cell membrane in tissues involved in absorption, distribution and excretion, such as the intestine, heart and kidney . Therefore, P‐gp plays an important role in determining the bioavailability of drugs, especially the orally administered drugs . In addition, P‐gp is also overexpressed in tumour cells, which is one major reason for the generation of multi‐drug resistance (MDR) in chemotherapy .…”

“…Therefore, P‐gp plays an important role in determining the bioavailability of drugs, especially the orally administered drugs . In addition, P‐gp is also overexpressed in tumour cells, which is one major reason for the generation of multi‐drug resistance (MDR) in chemotherapy . Hence, drugs interacted with P‐gp may probably affect the P‐gp‐mediated drug transport.…”

Enhanced oral bioavailability of paclitaxel by solid dispersion granulation

“…In this study, authors used a new P-gp inhibitor HM30181, which is chemically 4-oxo-4H-chromene-2-carboxylic acid, [2-(2-2H-tetrazol-5-yl)-4,5-dimethoxyphenyl]amide and the structure of which could be referred elsewhere 58 . HM30181 is a novel third generation P-gp inhibitor currently under development, that inhibits P-gp transporters specifically in the intestinal endothelium with no systemic effects, whose effect has been confirmed in various preclinical studies and clinical trials [59][60][61][62][63] . The dose of HM30181 was set at 30 mg for one dog and was administered in form of tablets.…”