Digoxin-Inactivating Bacteria: Identification in Human Gut Flora

Saha,; Butler, VP; Hc, Neu; Lindenbaum, John

doi:10.1126/science.6836275

Cited by 220 publications

(114 citation statements)

References 12 publications

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“…For example, a specific intestinal bacteria Eggerthella lenta has the genetic machinery needed to inactivate the cardiac glycoside digoxin, so antibiotic administration increases serum digoxin concentrations (Lindenbaum et al, 1981;Saha et al, 1983). Bacteria in the colon cleave the prodrug sulfasalazine to 5-aminosalicylic acid (an anti-inflammatory drug) and sulfapyridine (an antibiotic), so ampicillin administration decreases the concentration of sulfapyridine in circulation (Houston et al, 1982).…”

Section: Introductionmentioning

confidence: 99%

RNA-Seq Quantification of Hepatic Drug Processing Genes in Germ-Free Mice

2015

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Intestinal bacteria have been shown to be important in regulating host intermediary metabolism and contributing to obesity. However, relatively less is known about the effect of intestinal bacteria on the expression of hepatic drug-processing genes in the host. This study characterizes the expression of hepatic drug-processing genes in germ-free (GF) mice using RNA-Seq. Total RNA were isolated from the livers of adult male conventional and GF C57BL/6J mice (n = 3 per group). In the livers of GF mice, the mRNA of the aryl hydrocarbon receptor target gene Cyp1a2 was increased 51%, and the mRNA of the peroxisome proliferator-activated receptor a (PPARa) target gene Cyp4a14 was increased 202%. Conversely, the mRNA of the constitutive androstane receptor (CAR) target gene Cyp2b10 was decreased 57%, and the mRNA of the pregnane X receptor target gene Cyp3a11 was decreased 87% in GF mice. Although other non-Cyp phase-1 enzymes in the livers of GF mice were only moderately affected, there was a marked down-regulation in the phase-2 enzymes glutathione S-transferases p1 and p2, as well as a marked up-regulation in the major bile acid transporters Na + -taurocholate cotransporting polypeptide and organic aniontransporting polypeptide 1b2, and the cholesterol transporter ATPbinding cassette transporter Abcg5/Abcg8. This study demonstrates that intestinal bacteria regulate the expression of a large number of drug-processing genes, which suggests that intestinal bacteria are responsible for some individual differences in drug responses.

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Section: Introductionmentioning

confidence: 99%

RNA-Seq Quantification of Hepatic Drug Processing Genes in Germ-Free Mice

2015

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“…However, digoxin, mainly the Lanoxin formulation, can undergo metabolism in a small minority of patients by enteric bacteria (Lindenbaum et al, 1981), in which a double bond in the digoxin lactone ring is reduced. Because gut flora activity can vary in patients, variable levels of digoxin can be absorbed (Saha et al, 1983). Drug-drug interactions (DDIs) resulting in alterations in digoxin plasma exposure have been largely attributed to changes in P-glycoprotein (P-gp) efflux activity in the gut, liver, and kidney (Cavet et al, 1996;Ernest et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

Digoxin Is Not a Substrate for Organic Anion-Transporting Polypeptide Transporters OATP1A2, OATP1B1, OATP1B3, and OATP2B1 but Is a Substrate for a Sodium-Dependent Transporter Expressed in HEK293 Cells

Taub¹,

Mease²,

Sane³

et al. 2011

Drug Metab Dispos

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ABSTRACT:Digoxin, an orally administered cardiac glycoside cardiovascular drug, has a narrow therapeutic window. Circulating digoxin levels (maximal concentration of ϳ1.5 ng/ml) require careful monitoring, and the potential for drug-drug interactions (DDI) is a concern. Increases in digoxin plasma exposure caused by inhibition of Pglycoprotein (P-gp) have been reported. Digoxin has also been described as a substrate of various organic anion-transporting polypeptide (OATP) transporters, posing a risk that inhibition of OATPs may result in a clinically relevant DDI similar to what has been observed for P-gp. Although studies in rats have shown that Oatps contribute to the disposition of digoxin, the role of OATPs in the disposition of digoxin in humans has not been clearly defined. Using two methods, Boehringer Ingelheim, GlaxoSmithKline, Pfizer, and Solvo observed that digoxin is not a substrate of OATP1A2, OATP1B1, OATP1B3, and OATP2B1. However, digoxin inhibited the uptake of probe substrates of OATP1B1 (IC 50 of 47 M), OATP1B3 (IC 50 > 8.1 M), and OATP2B1 (IC 50 > 300 M), but not OATP1A2 in transfected cell lines. It is interesting to note that digoxin is a substrate of a sodium-dependent transporter endogenously expressed in HEK293 cells because uptake of digoxin was significantly greater in cells incubated with sodium-fortified media compared with incubations conducted in media in which sodium was absent. Thus, although digoxin is not a substrate for the human OATP transporters evaluated in this study, in addition to P-gp-mediated efflux, its uptake and pharmacokinetic disposition may be partially facilitated by a sodium-dependent transporter.

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“…It has long been recognized that gut microbes contribute to the metabolism of numerous drugs (Sousa et al, 2008). One of the best characterized examples is reductive deactivation of the cardiac glycoside digoxin by Eubacterium lentum, a common anaerobe in the colon (Saha et al, 1983). Gut microbial cleavage of a hydrazine/hydrazone has been rare, however.…”

Section: Discussionmentioning

confidence: 99%

Investigations of Hydrazine Cleavage of Eltrombopag in Humans

Deng¹,

Rogers²,

Sychterz³

et al. 2011

Drug Metab Dispos

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ABSTRACT:After oral administration to humans, eltrombopag undergoes extensive cleavage of its hydrazine linkage to metabolites, which are exclusively eliminated in urine. In vitro, the cleavage pathway was not detected in systems using cytochrome P450 enzymes, renal or hepatic microsomes, or hepatocytes but was readily evident after anaerobic incubation with rodent cecal contents or human fecal homogenate. Antibiotic treatment in vitro and in vivo inhibited eltrombopag cleavage, further indicating that cleavage is via gut microbes. Antibiotic treatment did not alter the systemic exposure of eltrombopag in mice. Oral and intravenous pharmacokinetic characterization in the mice with one of the cleavage products indicated that it was readily absorbed, conjugated, and eliminated in urine, consistent with its fate after oral administration of eltrombopag. Variation in this microbial pathway, for example by antibiotic cotherapy, is unlikely to be clinically significant.

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Digoxin-Inactivating Bacteria: Identification in Human Gut Flora

Cited by 220 publications

References 12 publications

RNA-Seq Quantification of Hepatic Drug Processing Genes in Germ-Free Mice

RNA-Seq Quantification of Hepatic Drug Processing Genes in Germ-Free Mice

Digoxin Is Not a Substrate for Organic Anion-Transporting Polypeptide Transporters OATP1A2, OATP1B1, OATP1B3, and OATP2B1 but Is a Substrate for a Sodium-Dependent Transporter Expressed in HEK293 Cells

Investigations of Hydrazine Cleavage of Eltrombopag in Humans

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