Involvement of the intestinal microflora in nitrazepam‐induced teratogenicity in rats and its relationship to nitroreduction

Takeno, Sachio; Sakai, Takeshi

doi:10.1002/tera.1420440209

Cited by 59 publications

(43 citation statements)

References 16 publications

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“…2) (ref. 63 ). in this case, the bacterial metabolic activation does not produce pharmacologically active metabolite but products with teratogenic effects.…”

Section: Nitro Reductionmentioning

confidence: 99%

Human gut microbiota plays a role in the metabolism of drugs

Jourová¹,

Anzenbacher²,

Anzenbacherová³

2016

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub

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a Background and Aims. The gut microbiome, an aggregate genome of trillions of microorganisms residing in the human gastrointestinal tract, is now known to play a critical role in human health and predisposition to disease. It is also involved in the biotransformation of xenobiotics and several recent studies have shown that the gut microbiota can affect the pharmacokinetics of orally taken drugs with implications for their oral bioavailability. Methods. Review of Pubmed, Web of Science and Science Direct databases for the years 1957-2016. Results and Conclusions. Recent studies make it clear that the human gut microbiota can play a major role in the metabolism of xenobiotics and, the stability and oral bioavailability of drugs. Over the past 50 years, more than 30 drugs have been identified as a substrate for intestinal bacteria. Questions concerning the impact of the gut microbiota on drug metabolism, remain unanswered or only partially answered, namely (i) what are the molecular mechanisms and which bacterial species are involved? (ii) What is the impact of host genotype and environmental factors on the composition and function of the gut microbiota, (iii) To what extent is the composition of the intestinal microbiome stable, transmissible, and resilient to perturbation? (iv) Has past exposure to a given drug any impact on future microbial response, and, if so, for how long? Answering such questions should be an integral part of pharmaceutical research and personalised health care.

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“…2) (ref. 63 ). in this case, the bacterial metabolic activation does not produce pharmacologically active metabolite but products with teratogenic effects.…”

Section: Nitro Reductionmentioning

confidence: 99%

Human gut microbiota plays a role in the metabolism of drugs

Jourová¹,

Anzenbacher²,

Anzenbacherová³

2016

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub

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“…Suppression of the nitroreductase activity of the gut microbiota by antibiotics before the administration of nitrazepam significantly decreased the urinary and fecal excretion of the two reduced metabolites from 30% to 2% and markedly reduced the incidence of teratogenicity. This underscores the roles of gut microbiota in nitrazepam-induced teratogenicity (Takeno and Sakai, 1991). Lovastatin is a lactone prodrug that is used in the treatment of hypercholesterolemia.…”

Section: Host-gut Microbiota Modulation Of Therapeutic Outcomementioning

confidence: 93%

“…Nitrazepam, a benzodiazepine drug, has been reported to induce teratogenicity (Takeno and Sakai, 1991). Incubation of nitrazepam with bacterial suspensions prepared from rat cecal contents resulted in extensive reduction to 7-aminonitrazepam, which in turn yielded 7-acetylaminonitrazepam via hepatic acetylation.…”

Section: Host-gut Microbiota Modulation Of Therapeutic Outcomementioning

confidence: 99%

Investigation of Host–Gut Microbiota Modulation of Therapeutic Outcome

Yip

Chan

2015

Drug Metab Dispos

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A broader understanding of factors underlying interindividual variation in pharmacotherapy is important for our pursuit of "personalized medicine." Based on knowledge gleaned from the investigation of human genetics, drug-metabolizing enzymes, and transporters, clinicians and pharmacists are able to tailor pharmacotherapies according to the genotype of patients. However, human host factors only form part of the equation that accounts for heterogeneity in therapeutic outcome. Notably, the gut microbiota possesses wide-ranging metabolic activities that expand the metabolic functions of the human host beyond that encoded by the human genome. In this review, we first illustrate the mechanisms in which gut microbes modulate pharmacokinetics and therapeutic outcome. Second, we discuss the application of metabonomics in deciphering the complex host-gut microbiota interaction in pharmacotherapy. Third, we highlight an integrative approach with particular mention of the investigation of gut microbiota using culture-based and culture-independent techniques to complement the investigation of the host-gut microbiota axes in pharmaceutical research.

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“…The incidence of nitrazepam-induced malformations was also markedly reduced by the antibiotic treatment. This suggests that the intestinal microflora reduces nitrazepam to 7-aminonitrazepam, which is responsible for the teratogenicity (Takeno et al, 1990;Takeno and Sakai, 1991).…”

Section: Intestinal Microbiota Metabolizes Drug To a Teratogenmentioning

confidence: 99%

Review: Mechanisms of How the Intestinal Microbiota Alters the Effects of Drugs and Bile Acids

2015

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Information on the intestinal microbiota has increased exponentially this century because of technical advancements in genomics and metabolomics. Although information on the synthesis of bile acids by the liver and their transformation to secondary bile acids by the intestinal microbiota was the first example of the importance of the intestinal microbiota in biotransforming chemicals, this review will discuss numerous examples of the mechanisms by which the intestinal microbiota alters the pharmacology and toxicology of drugs and other chemicals. More specifically, the altered pharmacology and toxicology of salicylazosulfapridine, digoxin, L-dopa, acetaminophen, caffeic acid, phosphatidyl choline, carnitine, sorivudine, irinotecan, nonsteroidal anti-inflammatory drugs, heterocyclic amines, melamine, nitrazepam, and lovastatin will be reviewed. In addition, recent data that the intestinal microbiota alters drug metabolism of the host, especially Cyp3a, as well as the significance and potential mechanisms of this phenomenon are summarized. The review will conclude with an update of bile acid research, emphasizing the bile acid receptors (FXR and TGR5) that regulate not only bile acid synthesis and transport but also energy metabolism. Recent data indicate that by altering the intestinal microbiota, either by diet or drugs, one may be able to minimize the adverse effects of the Western diet by altering the composition of bile acids in the intestine that are agonists or antagonists of FXR and TGR5. Therefore, it may be possible to consider the intestinal microbiota as another drug target.

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Involvement of the intestinal microflora in nitrazepam‐induced teratogenicity in rats and its relationship to nitroreduction

Cited by 59 publications

References 16 publications

Human gut microbiota plays a role in the metabolism of drugs

Human gut microbiota plays a role in the metabolism of drugs

Investigation of Host–Gut Microbiota Modulation of Therapeutic Outcome

Review: Mechanisms of How the Intestinal Microbiota Alters the Effects of Drugs and Bile Acids

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