An investigation of the metabolic activity, isozyme contribution, species differences and potential drug–drug interactions of PI-103, and the identification of efflux transporters for PI-103-<i>O</i>-glucuronide in HeLa1A9 cells

Gao, Li; Qin, Z. H.; Zhang, Beibei; Zhao, Yin; Zhang, Xiaojian; Yang, Jing

doi:10.1039/c9ra09906a

Cited by 9 publications

(31 citation statements)

References 40 publications

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“…5F) and D5 towards CYP2C9 (Fig. 5G) [18]. In this study, [I]/K i values for these herbal compounds were all no more than 0.1 (Table 2).…”

Section: Analysis Of Inhibition Mechanismmentioning

confidence: 48%

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Multiple circulating alkaloids and saponins from intravenous Kang-Ai injection inhibit human cytochrome P450 and UDP-glucuronosyltransferase isozymes: potential drug-drug interactions

Qin¹,

Jia

Yang

et al. 2020

Preprint

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Background: Kang-Ai injection is widely used as an adjuvant therapy drug for many cancers, leukopenia, and chronic hepatitis B. Circulating alkaloids and saponins are believed to be responsible for therapeutic effects. However, their pharmacokinetics (PK) and excretion in vivo and the risk of drug-drug interactions (DDI) through inhibiting human cytochrome P450 (CYP) and UDP-glucuronosyltransferase (UGT) enzymes remain unclear. Methods: PK and excretion of circulating compounds were investigated in rats using a validated ultra-high-performance liquid chromatography tandem mass spectrometry (UHPLC-MS) method. Further, the inhibitory effects of nine major compounds against eleven CYP and UGT isozymes were assayed using well-accepted specific substrate for each enzyme. Results: After dosing, 9 alkaloids were found with Cmax and t1/2 values of 0.17-422.70 μmol/L and 1.78-4.33 h, respectively. Additionally, 28 saponins exhibited considerable systemic exposure with t1/2 values of 0.63-7.22 h, whereas other trace saponins could be negligible or undetected. Besides, over 90% of alkaloids were excreted through hepatobiliary and renal excretion. Likewise, astragalosides and protopanaxatriol (PPT) type ginsenosides also involved in hepatobiliary and/or renal excretion. Protopanaxadiol (PPD) type ginsenosides were mainly excreted to urine. Furthermore, PPD-type ginsenosides were extensively bound (fu-plasma approximately 1%), whereas astragalosides and PPT-type ginsenosides displayed fu-plasma values of 12.35% and 60.23-87.36%, respectively. Moreover, matrine, oxymatrine, astragaloside IV, ginsenoside Rg1, ginsenoside Re, ginsenoside Rd, ginsenoside Rc, and ginsenoside Rb1 exhibited no inhibition or weak inhibition against several common CYP and UGT enzymes IC50 values between 8.81 and 92.21 μM. Through kinetic modeling, their inhibition mechanisms towards those CYP and UGT isozymes were explored with obtained Ki values. In vitro-in vivo extrapolation showed the inhibition of systemic clearance for CYP or UGT substrates seemed impossible due to [I]/Ki no more than 0.1.Conclusions: We summarized the PK behaviors, excretion characteristics and protein binding rates of circulating alkaloids, astragalosides and ginsenosides after intravenous Kang-Ai injection. Furthermore, weak inhibition or no inhibition towards these CYP and UGT activities could not trigger harmful DDI when Kang-Ai injection is co-administered with clinical drugs primarily cleared by these CYP or UGT isozymes.

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“…5F) and D5 towards CYP2C9 (Fig. 5G) [18]. In this study, [I]/K i values for these herbal compounds were all no more than 0.1 (Table 2).…”

Section: Analysis Of Inhibition Mechanismmentioning

confidence: 48%

“…The inhibition constant (K i ) values were obtained by multiple concentrations of substrates in the absence or presence of multiple concentrations of herbal compounds as described previously [18,27,28].…”

Section: Inhibition Kinetic Analysismentioning

confidence: 99%

Multiple circulating alkaloids and saponins from intravenous Kang-Ai injection inhibit human cytochrome P450 and UDP-glucuronosyltransferase isozymes: potential drug-drug interactions

Qin¹,

Jia

Yang

et al. 2020

Preprint

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“…27,30 Similarly, b-estradiol (60 mM), propofol (40 mM) and zidovudine (500 mM) were typically used as the selective probe substrates for UGT1A1, 1A9, and 2B7, respectively. 31,32 The substrates above were separately incubated with CYP isozyme (or UGT enzymes) in the absence (control) and presence of bavachinin (1, 10, 100 mM) at optimized incubation time and protein concentration as described previously. 27,[30][31][32] The half-inhibition concentration (IC 50 ) values of bavachinin towards individual CYP and UGT isozyme were obtained using the non-linear regression analysis.…”

Section: Inhibitory Effects Of Bavachinin Against Cyp and Ugt Isozymesmentioning

confidence: 99%

“…31,32 The substrates above were separately incubated with CYP isozyme (or UGT enzymes) in the absence (control) and presence of bavachinin (1, 10, 100 mM) at optimized incubation time and protein concentration as described previously. 27,[30][31][32] The half-inhibition concentration (IC 50 ) values of bavachinin towards individual CYP and UGT isozyme were obtained using the non-linear regression analysis. Traditionally, the inhibitory effects could be divided into four categories based on the IC 50 values as follows: potent (less than 1 mM), moderate (between 1 and 10 mM), weak (over 10 mM), or no inhibition (over 100 mM).…”

Section: Inhibitory Effects Of Bavachinin Against Cyp and Ugt Isozymesmentioning

confidence: 99%

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Potential metabolism determinants and drug–drug interactions of a natural flavanone bavachinin

Xing

Qin

et al. 2020

RSC Adv.

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Arming Immune Cell Therapeutics with Polymeric Prodrugs

Lopez

Brempelis

Matthaei³

et al. 2021

Adv Healthcare Materials

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Engineered immune cells are an exciting therapeutic modality, which survey and attack tumors. Backpacking strategies exploit cell targeting capabilities for delivery of drugs to combat tumors and their immune‐suppressive environments. Here, a new platform for arming cell therapeutics through dual receptor and polymeric prodrug engineering is developed. Macrophage and T cell therapeutics are engineered to express a bioorthogonal single chain variable fragment receptor. The receptor binds a fluorescein ligand that directs cell loading with ligand‐tagged polymeric prodrugs, termed “drugamers.” The fluorescein ligand facilitates stable binding of drugamer to engineered macrophages over 10 days with 80% surface retention. Drugamers also incorporate prodrug monomers of the phosphoinositide‐3‐kinase inhibitor, PI‐103. The extended release of PI‐103 from the drugamer sustains antiproliferative activity against a glioblastoma cell line compared to the parent drug. The versatility and modularity of this cell arming system is demonstrated by loading T cells with a second fluorescein‐drugamer. This drugamer incorporates a small molecule estrogen analog, CMP8, which stabilizes a degron‐tagged transgene to provide temporal regulation of protein activity in engineered T cells. These results demonstrate that this bioorthogonal receptor and drugamer system can be used to arm multiple immune cell classes with both antitumor and transgene‐activating small molecule prodrugs.

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An investigation of the metabolic activity, isozyme contribution, species differences and potential drug–drug interactions of PI-103, and the identification of efflux transporters for PI-103-O-glucuronide in HeLa1A9 cells

Abstract: Metabolic activity and disposition characteristics of PI-103.

Cited by 9 publications

References 40 publications

Multiple circulating alkaloids and saponins from intravenous Kang-Ai injection inhibit human cytochrome P450 and UDP-glucuronosyltransferase isozymes: potential drug-drug interactions

Multiple circulating alkaloids and saponins from intravenous Kang-Ai injection inhibit human cytochrome P450 and UDP-glucuronosyltransferase isozymes: potential drug-drug interactions

Potential metabolism determinants and drug–drug interactions of a natural flavanone bavachinin

Arming Immune Cell Therapeutics with Polymeric Prodrugs

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