Metabolic Switching of BILR 355 in the Presence of Ritonavir. II. Uncovering Novel Contributions by Gut Bacteria and Aldehyde Oxidase

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18 metabolites was observed. Their structures were proposed on the basis of high-performance liquid chromatography-tandem mass spectrometry technologies, and 10 metabolites were confirmed by comparison with synthetic standards. We were surprised to find that a disproportionate human metabolite, BILR 516, was uncovered during this metabolite profiling study and pharmacokinetic analysis of BILR 516 showed that it had a longer half-life and higher exposure than the parent compound at steady state. Of interest, BILR 516 was not detected in human plasma when BILR 355 was administered alone. Therefore, whereas RTV boosted the exposure of BILR 355, it resulted in a significant metabolic switching of BILR 355. Overall, this article demonstrates an unusual example of metabolic switching and raises concern about the consequence of metabolic switching during drug development.

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Metabolic Switching of BILR 355 in the Presence of Ritonavir. I. Identifying an Unexpected Disproportionate Human Metabolite

Li¹,

Lai²,

Whitcher-Johnstone³

et al. 2012

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“…Bacterially mediated N-oxide reduction lies at the core of an interesting interplay between the host and microbial enzymes in the metabolism of BILR355, an inhibitor of the human immunodeficiency virus (Li et al, 2012). BILR355 is extensively metabolized by CYP3A; however, study of the concomitant administration of ritonavir with BILR355 uncovered dmd.aspetjournals.org a unique metabolic role of gut bacteria and aldehyde oxidase.…”

Section: Impact Of the Gut Microbiome On The Metabolism And Pharmacokmentioning

confidence: 99%

Drug Metabolism by the Host and Gut Microbiota: A Partnership or Rivalry?

Swanson

2015

140

The importance of the gut microbiome in determining not only overall health, but also in the metabolism of drugs and xenobiotics, is rapidly emerging. It is becoming increasingly clear that the gut microbiota can act in concert with the host cells to maintain intestinal homeostasis, cometabolize drugs and xenobiotics, and alter the expression levels of drug-metabolizing enzymes and transporters and the expression and activity levels of nuclear receptors. In this myriad of activities, the impact of the microbiota may be beneficial or detrimental to the host. Given that the interplay between the gut microbiota and host cells is likely subject to high interindividual variability, this work has tremendous implications for our ability to predict accurately a particular drug's pharmacokinetics and a given patient population's response to drugs. In this issue of Drug Metabolism and Disposition, a series of articles is presented that illustrate the progress and challenges that lie ahead as we unravel the intricacies associated with drug and xenobiotic metabolism by the gut microbiota. These articles highlight the underlying mechanisms that are involved and the use of in vivo and in vitro approaches that are currently available for elucidating the role of the gut microbiota in drug and xenobiotic metabolism. These articles also shed light on exciting new avenues of research that may be pursued as we consider the role of the gut microbiota as an endocrine organ, a component of the brain-gut axis, and whether the gut microbiota is an appropriate and amenable target for new drugs.

“…The supernatant was transferred to each well and preincubated for 5 minutes at 37°C. Reactions were initiated by the addition of faldaprevir (final concentration 50 mM) to each well and conducted under either aerobic or anaerobic conditions (Li et al, 2012) at 37°C. Final organic solvent concentration in each reaction was 1%.…”

Section: Incubation With Human Gut Contentmentioning

confidence: 99%

Enzyme-Transporter Interplay in the Formation and Clearance of Abundant Metabolites of Faldaprevir Found in Excreta but not in Circulation

Zhou

Ramsden

et al. 2013

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Faldaprevir is a hepatitis C virus protease inhibitor that effectively reduces viral load in patients. Since faldaprevir exhibits slow metabolism in vitro and low clearance in vivo, metabolism was expected to be a minor clearance pathway. The human [14 C] absorption, distribution, metabolism, and excretion study revealed that two monohydroxylated metabolites (M2a and M2b) were the most abundant excretory metabolites in feces, constituting 41% of the total administered dose. To deconvolute the formation and disposition of M2a and M2b in humans and determine why the minor change in structure [the addition of 16 atomic mass units (amu)] produced chemical entities that were excreted and were not present in the circulation, multiple in vitro test systems were used. The results from these in vitro studies clarified the formation and clearance of M2a and M2b. Faldaprevir is metabolized primarily in the liver by CYP3A4/5 to form M2a and M2b, which are also substrates of efflux transporters (P-glycoprotein and breast cancer resistance protein). The role of transporters is considered important for M2a and M2b as they demonstrate low permeability. It is proposed that both metabolites are efficiently excreted via bile into feces and do not enter the systemic circulation to an appreciable extent. If these metabolites permeate to blood, they can be readily taken up into hepatocytes from the circulation by uptake transporters (likely organic anion transporting polypeptides). These results highlight the critical role of drug-metabolizing enzymes and multiple transporters in the process of the formation and clearance of faldaprevir metabolites. Faldaprevir metabolism also provides an interesting case study for metabolites that are exclusively excreted in feces but are of clinical relevance.