Impact of gut microbiota on drug metabolism: an update for safe and effective use of drugs

Noh, Keumhan; Kang, You Ra; Nepal, Mahesh Raj; Shakya, Rajina; Kang, Mi Jeong; Kang, Wonku; Lee, Sangkyu; Jeong, Hye Gwang; Jeong, Tae Cheon

doi:10.1007/s12272-017-0986-y

Cited by 60 publications

(40 citation statements)

References 59 publications

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“…The gut microbiota is affected by drug dosages, pharmaceutical compositions, length of treatment course, and adjuvant use (Noh et al., 2017). At the same time, the changes in the gut microbiota may change the pharmacokinetic characteristics of the therapeutic drug.…”

Section: Resultsmentioning

confidence: 99%

Auxiliary antitumor effects of fungal proteins from Hericium erinaceus by target on the gut microbiota

Wang

Zhu

Tang

et al. 2020

Journal of Food Science

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Cancer represents a major disease burden worldwide. Despite continuous advances obtained in medical therapies recently, resistance to standard drugs and adverse effects still represent important causes of therapeutic failure. There is growing evidence that the gut microbiota can affect the response to chemo‐ and immunotherapeutic drugs by modulating efficacy and/or toxicity, and diet is the most important factor affecting the gut microbiota. In this study, we assessed the auxiliary antitumor effects of immunomodulatory fungal proteins from Hericium erinaceus (HEP) administered with the chemotherapy drug 5‐Fluorouracil (5‐Fu), and we attempted to identify new potential prebiotic bacteria for auxiliary antitumor treatment. There were 1,455 proteins identified from H. erinaceus. In a xenografted mouse model of cancer, HEP with 5‐Fu significantly suppressed tumor growth, inhibited inflammatory markers such as interferon (IFN)‐γ, interleukin (IL)‐1β, IL‐2, IL‐6, tumor necrosis factor (TNF)‐α, and lipopolysaccharide (LPS), and regulated the expression of Akt, CCDN1, CKD4, FOXM1, MMP7, MYC, PPAR‐α, and PPAR‐γ. 16S rRNA sequencing showed that HEP ameliorated the dysbacteriosis induced by 5‐Fu, as it inhibited certain aerobic and microaerobic bacteria including Parabacteroides, Flavobacteriaceae, Christensenellaceae, Anoxybacillus, Aggregatibacter, Comamonadaceae, Planococcaceae, Desulfovibrionaceae, Sporosarcina, Staphylococcus, Aerococcaceae, and Bilophila in the xenografted mice, and increase some probiotic bacteria such as Bifidobacterium, Gemellales, Blautia, Sutterella, Anaerostipes, Roseburia, Lachnobacterium, Lactobacillus, and Desulfovibrio. This demonstrates that HEP could promote the antitumor efficacy of 5‐Fu by improving the microbiota composition, the immune inflammatory response, and homeostasis.

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Section: Resultsmentioning

confidence: 99%

Auxiliary antitumor effects of fungal proteins from Hericium erinaceus by target on the gut microbiota

Wang

Zhu

Tang

et al. 2020

Journal of Food Science

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“…Additionally, p ‐cresol, an endogenous microbial metabolite, undergoes sulfation and can diminish APAP sulfation by competitive inhibition . Finally, Hendrickson et al reported that APAP can undergo enterohepatic circulation, whereby APAP‐gluc is deconjugated by microbial‐expressed β‐glucuronidase prior to reabsorption . Disrupting enterohepatic circulation can lead to decreases in APAP half‐life, resulting in lower APAP exposure.…”

Section: Discussionmentioning

confidence: 99%

The Impact of Proximal Roux‐en‐Y Gastric Bypass Surgery on Acetaminophen Absorption and Metabolism

et al. 2020

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Background Roux‐en‐Y gastric bypass (RYGBS), a surgery that creates a smaller stomach pouch and reduces the length of small intestine, is one of the most common medical interventions for the treatment of obesity. Aim The aim of this study was to determine how RYGBS affects the absorption and metabolism of acetaminophen. Materials and Methods Ten morbidly obese patients received 1.5 g of liquid acetaminophen (APAP) orally on three separate pharmacokinetic study days (i.e., pre‐RYGBS baseline and 3 and 12 months post‐RYGBS). Plasma was collected at pre‐specified timepoints over 24 hours, and the samples were analyzed using liquid chromatography–mass spectrometry for APAP, APAPglucuronide (APAP‐gluc), APAP‐sulfate (APAP‐sulf), APAP‐cysteine (APAP‐cys), and APAP‐Nacetylcysteine (APAP‐nac). Result Following RYGBS, peak APAP concentrations at the 3‐month and 12‐month visits increased by 2.0‐fold compared to baseline (p=0.0039 and p=0.0078, respectively) and the median time to peak concentration decreased from 35 to 10 minutes. In contrast, peak concentrations of APAP‐gluc, APAP‐sulf, APAP‐cys, and APAP‐nac were unchanged following RYGBS. The apparent oral clearance of APAP and the ratios of metabolite area under the curve (AUC)‐to‐APAP AUC for all four metabolites decreased at 3 and 12 months post‐RYGBS compared to the presurgical baseline. In a simulation of expected steady‐state plasma concentrations following multiple dosing of 650 mg APAP every 4 hours, post‐RYGBS patients had higher steady‐state peak APAP concentrations compared to healthy individuals and obese pre‐RYGBS patients, though APAP exposure was unchanged compared to healthy individuals. Conclusion Following RYGBS, the rate and extent of APAP absorption increased and decreased formation of APAP metabolites was observed, possibly due to downregulation of Phase II and cytochrome P450 2E1 enzymes.

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“…Interestingly, no such phenomenon was observed in any of the concentration–time profiles in the present study in rats, which might point to species-related differences in metabolism and excretion routes. Among other factors, the impact of enterohepatic circulation of a drug on its plasma concentration depends on rate and extent of breakdown of glucuronidated or otherwise conjugated compound by intestinal microbiota [ 28 ]. Substantial compositional diversity of the gut microbiota has been reported previously [ 29 ].…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics of the P-gp Inhibitor Tariquidar in Rats After Intravenous, Oral, and Intraperitoneal Administration

Matzneller

Kussmann

Eberl

et al. 2018

Eur J Drug Metab Pharmacokinet

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Background and objectiveP-glycoprotein (P-gp), a transmembrane transporter expressed at the blood–brain barrier, restricts the distribution of diverse central nervous system-targeted drugs from blood into brain, reducing their therapeutic efficacy. The third-generation P-gp inhibitor tariquidar (XR9576) was shown to enhance brain distribution of P-gp substrate drugs in humans. Oral bioavailability of tariquidar was found to be low in humans requiring the compound to be administered intravenously, which hinders a broader clinical use. The objective of the present study was to investigate the plasma pharmacokinetics of tariquidar in rats after single intravenous, oral, and intraperitoneal administration.MethodsTwo different tariquidar formulations (A and B) were used, both at a dosage of 15 mg/kg, respectively. Formulation A was a solution and formulation B was a microemulsion which was previously shown to improve the oral bioavailability of the structurally related P-gp inhibitor elacridar in mice.ResultsIn contrast to human data, the present study found a high bioavailability of tariquidar in rats after oral dosing. Oral bioavailability was significantly higher (p = 0.032) for formulation B (86.3%) than for formulation A (71.6%). After intraperitoneal dosing bioavailability was 91.4% for formulation A and 99.6% for formulation B.ConclusionThe present findings extend the available information on tariquidar and provide a basis for future studies involving oral administration of this compound.

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Impact of gut microbiota on drug metabolism: an update for safe and effective use of drugs

Cited by 60 publications

References 59 publications

Auxiliary antitumor effects of fungal proteins from Hericium erinaceus by target on the gut microbiota

Auxiliary antitumor effects of fungal proteins from Hericium erinaceus by target on the gut microbiota

The Impact of Proximal Roux‐en‐Y Gastric Bypass Surgery on Acetaminophen Absorption and Metabolism

Pharmacokinetics of the P-gp Inhibitor Tariquidar in Rats After Intravenous, Oral, and Intraperitoneal Administration

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