**1. Introduction**

Compound K, which belongs to the protopanaxadiol (PPD)-type ginsenoside group, was first discovered in 1972 from a hydrolase mixture of ginsenosides (Rb1, Rb2, and Rc) and soil bacteria [1]. Since then, compound K has attracted special attention among the various ginsenosides because it is reported as a major pharmacologically active component that has hepatoprotective, chemo-preventive, anti-diabetic, anti-inflammatory, anti-arthritic, neuroprotective, and immune stimulating effects [1,2]. The therapeutic benefit of compound K has been demonstrated in both in vitro studies and in vivo disease models [1]. Paek et al. [3] investigated the dose-dependent bioavailability of compound K by comparing its oral and intravenous administration in rats. The area under plasma concentration (AUC) of compound K increased linearly following intravenous injection at a dose range of 1–10 mg/kg (dose increase 10-fold; AUC increase 11.6-fold), but the AUC of compound K following oral administration did not increase linearly at a dose range of 5–20 mg/kg (dose increase four-fold; AUC increase 75.8-fold) [3]. The AUC of compound K was significantly increased (23.5-fold) in P-glycoprotein (P-gp) knock-out mice compared to wild-type mice after a single oral dose (10 mg/kg) [4]. Therefore,

P-gp-mediated efflux during intestinal absorption could be a possible explanation for non-linear oral bioavailability of compound K.

The safety, pharmacokinetics, and preliminary efficacy of compound K in tablet form as an anti-rheumatoid arthritis drug are under clinical investigation in China (Study No. NCT03755258) [5]. In this study, Chen et al. [5] investigated the pharmacokinetics of compound K and PPD, a metabolite of compound K, following a single oral administration of a 200 mg compound K tablet. This was the first pharmacokinetic study in humans using pure compound K. The maximum plasma concentration (*C*max) of compound K was 796.8 ng/mL with a time to reach *C*max (*T*max) of 3.6 h. On the other hand, the *C*max of PPD was 5.7 ng/mL with a *T*max of 24.5 h. The results suggested that the formation of PPD from compound K occurred slowly. The AUC ratio of PPD to compound K was calculated as 0.04 [5]. They also investigated the effect of high-fat meal on the pharmacokinetics of compound K. The high-fat meal consumption increased *C*max (2.0-fold) and AUC (2.2-fold) of compound K but decreased *T*max (3.6 h in fasting group vs. 2.5 h in high-fat meal group, *p* < 0.05) compared with fasting group, suggesting that the high-fat meal accelerated the absorption of compound K [5].

Other pharmacokinetic studies of compound K have been reported in human subjects following oral administration of ginseng product [2,6–9]. The *C*max of compound K was 41.5 ng/mL in 12 Japanese subjects following a single oral administration of fermented ginseng tablet (274.4 mg total; 2.2 mg as compound K) [6]. The mean *C*max (254.5 ng/mL) was substantially higher and less variable in subjects who were orally administered fermented Korean red ginseng (3 g total; 10.9 mg as compound K) than the *C*max (3.2–24.8 ng/mL) in subjects who received non-fermented Korean red ginseng extract (3 g total; 0 mg as compound K) [2,7,9]. The results suggested that the consumption of ginseng product with higher compound K content resulted in higher plasma concentrations of compound K. The compound K in the plasma was absorbed after the metabolism from Rb1, Rb2, Rc, and Rd (major components of red ginseng product) to compound K following oral administration of non-fermented red ginseng product [7,10]. Therefore, the variability in the gut metabolism and intestinal absorption of compound K could be attributed to the variable plasma concentrations of compound K. However, little information is available on the distribution and elimination of compound K. Therefore, the purpose of this study was to investigate the pharmacokinetics of compound K in rats and mice with a focus on tissue distribution, elimination, and metabolism to PPD.
