Polypodium leucotomos PL is a fern native to Latin America, and its extract is used as an oral sunscreen ; however, its safety during use has not been adequately investigated. Therefore, the aim of this study was to evaluate fooddrug interactions associated with PL extract mediated by cytochrome P450 3A CYP3A inhibition and induction. Inhibition of CYP3A-mediated midazolam MDZ 1-hydroxylation activity by PL extract and its major phenolic components was evaluated in vitro using pooled human liver microsomes. In addition, MDZ pharmacokinetics were investigated in rats after a single dose, as well as after 1 week treatment with PL extract 30 mg / kg in order to evaluate the inhibitory and inducible effects of PL on CYP3A in vivo, respectively. Serum MDZ concentrations were analyzed and pharmacokinetic parameters were compared between PL-and water control-treated groups. In vitro, PL extract decreased MDZ 1-hydroxylation activity in a concentration-dependent manner. However, the major phenolic compounds in PL extracts, namely caffeic, chlorogenic, p-coumaric, ferulic, and vanillic acids, did not exhibit any marked inhibitory effects on MDZ 1-hydroxylation activity. In vivo, administration of a single dose of PL extract to rats signi cantly increased the area under the serum concentration-time curve from time 0 to infinity AUC 0-and the maximum serum concentration C max of MDZ by 57 and 88 , respectively ; P 0.05. In contrast, there were no signi cant changes in MDZ pharmacokinetic parameters after 1 week of treatment with PL extract. These results suggest that PL extract can cause a food-drug interaction by inhibiting CYP3A.

The concept of lichenoid tissue reactions (LTR) was proposed by Pinkus in 1973. 1 LTR refer to reactions in which epidermal keratinocytes are damaged by inflammatory cells infiltrating into the dermis, resulting in vacuolar or liquefaction degeneration of basal cells, and cell death/individual keratinization of keratinocytes. 1 LTR are classified into those with prominent (cell rich) and those with little (cell poor) cell infiltration. The prototype of the former reaction is lichen planus. 2 Programmed cell death 1 (PD-1) is expressed on lymphocytes, binds to its ligands, programmed cell death ligand 1 (PD-L1), and PD-L2, and suppresses the regulation of lymphocyte function. 3 PD-L1 is expressed on leukocytes, especially macrophages, stromal cells, and tumor cells, 4 and PD-L2 is mainly expressed on dendritic cells. 4PD-1 antagonists activate lymphocytes to treat malignant tumors.In recent years, immune checkpoint inhibitors (ICI), such as PD-1 and PD-L1 inhibitors, have been developed and used in the immunotherapy of solid cancers following malignant melanoma. With the use of ICI, a variety of immune-related adverse events (irAE), including lichen planus/lichenoid eruption, have been reported. 5 The aim of this study was to clarify the role of PD-1 and PD-L1 in the pathogenesis of lichen planus in the absence of ICI administration, using biopsy specimens.

The extract of Polypodium leucotomos is used as a dietary supplement for its ultraviolet radiation-protective properties. Polypodium leucotomos extract reportedly inhibits CYP3A, which is important for drug metabolism in vitro in human microsomes and in vivo in rats.In this study, we explored the inhibitory effect of the P. leucotomos extract on CYP3A4mediated midazolam metabolism in humans. This open-label, two-period, fixed-sequence study was performed on six healthy, Japanese, male volunteers. During period 1 (control), midazolam (1 mg) was orally administered. After a wash-out period of at least 5 days, period 2 was initiated. Subjects ingested P. leucotomos extract (240 mg) once in the morning and once at noon on the day before midazolam administration, and once the next morning (thrice overall). Midazolam was administered as in period 1. Blood samples were regularly collected for 8 hours after drug administration, and serum midazolam concentration was determined by ultra-fast liquid chromatography-tandem mass spectrometry. The pharmacokinetic parameters of midazolam were calculated and compared between the two periods. The area under the concentration-time curve was 19.18 AE 3.65 ng h/ml, maximum serum concentration was 7.81 AE 1.25 ng/ml, and half-life was 2.32 AE 0.35 hours during period 2. These parameters did not differ from those recorded in period 1 (area under the concentration-time curve: 18.74 AE 2.97 ng h/ml, maximum serum concentration: 8.78 AE 1.67 ng/ml, half-life: 2.52 AE 0.52 h). Therefore, short-term oral administration of P. leucotomos extract did not cause food-drug interactions mediated by CYP3A4 inhibition in humans.

Aim: Wood creosote (WC), an over-the-counter (OTC) drug, has been used as an anti-diarrheal agent for many years; however, its safety in combination with other drugs has not been adequately investigated. The current study was conducted to evaluate whether WC may cause drug interactions through the inhibition of cytochrome P450 (CYP). Methods: The inhibitory effects of WC on ethoxyresorufin O-deethylation, paclitaxel 6α-hydroxylation, S-warfarin 7-hydroxylation, S-mephenytoin 4 0 -hydroxylation, bufuralol1 0 -hydroxylation, and midazolam (MDZ) 1 0 -hydroxylation were investigated using human liver microsomes as the marker activities for CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4, respectively. In addition, the effects of single and three-day multiple treatments of WC (30 mg/kg) on CYP2C-mediated tolbutamide (TB, 20 mg/kg) and CYP3A-mediated MDZ (15 mg/kg) metabolism were investigated in rats in vivo.Results: WC at clinical doses did not show a considerable inhibitory effect on any of the CYP activities examined in the in vitro study. CYP2C9 and CYP2C19 activities were inhibited by high concentrations of the WC (100 μg/mL); however, the IC 50 values were approximately 70 times higher than the reported circulating levels of the main ingredients in WC. Furthermore, there were no marked changes in the pharmacokinetic parameters of TB and MDZ (area under the serum concentration-time curve, maximum serum concentrations, and elimination half-life) after single or three-day multiple treatments with WC. Conclusion: These results suggest that clinical doses of WC are unlikely to cause drug interactions mediated by the inhibition of CYPs.