A reader wrote about how a prescription drug effect on her varied greatly day by day. I recall that the microbiome can vary greatly day by day (from charts on http://richardsprague.com/ ). I thought I should visit this topic.

Many people know that grapefruit interacts with many drugs.

• Effect of grapefruit juice on drug metabolism in rats [1994].
• Grapefruit juice and drugs. How significant is the interaction? [1994]
• Acute effects of drinking grapefruit juice on the pharmacokinetics and dynamics of felodipine–and its potential clinical relevance [1992].
• Ingestion of grapefruit lowers elevated hematocrits in human subjects [1988].
• In vitro inhibition of midazolam and quinidine metabolism by flavonoids [1995].

Microbiome and Diet

Diet

Diet impacts the microbiome, whether the effects below are independent of the microbiome or due to temporal changes of the microbiome is unknown.

• Influence of diet and nutritional status on drug metabolism [1996].
  • ” It is well known that smoking, charcoal broiled food or cruciferous vegetables induce the metabolism of many xenobiotics, whereas grapefruit juice increases the oral bioavailability of the high clearance drugs nifedipine, nitrendipine or felodipine by inhibiting their presystemic (intestinal) elimination. Energy deficiency, and especially a low intake of protein, will cause a decrease of about 20 to 40% in phenazone and theophylline clearance and elimination of those drugs can be accelerated by a protein-rich diet. In the same way, protein deficiency induced by either vegetarian food or undernourishment will have the opposite pharmacokinetic consequences.”
• ” Feeding rats brussels sprouts or cabbage stimulates the intestinal and hepatic metabolism of drugs in animals. This effect is caused, at least in part, by certain indoles normally present in these vegetables. The feeding of a charcoal-broiled beef diet to rats stimulates the metabolism of phenacetin in vitro, and a similar diet stimulates the in vivo metabolism of phenacetin in man” [1977]
• “Several dietary factors influence the oxidative metabolism of chemicals in humans. Increasing the ratio of protein to carbohydrate or fat in the diet, feeding cabbage and brussels sprouts or feeding charcoal-broiled beef for several days stimulates human drug metabolism. The chronic ingestion of ethanol stimulates drug metabolism whereas the chronic ingestion of methylxanthine-containing foods inhibits drug metabolism. In contrast, an increase in the ratio of fat to carbohydrate in the diet of normal subjects or the fasting of obese individuals for several days has little or no effect on drug metabolism. Flavonoids in edible plants influence the metabolism of foreign chemicals by human liver in vitro. The addition of flavone, tangeretin or nobiletin to human liver microsomes activates both the hydroxylation of benzo[alpha]pyrene and the metabolism of aflatoxin B1 to mutagens. On the other hand, quercetin, kaempferol, morin and chrysin, which are also normally occurring flavonoids, inhibit the hydroxylation of benzo[alpha]pyrene by human liver microsomes.” [1980]

Microbiome

• “These data clearly illustrated that gut microbiome phenotypes significantly affected arsenic metabolic reactions, including reduction, methylation, and thiolation. These findings improve our understanding of how infectious diseases and environmental exposure interact and may also provide novel insight regarding the gut microbiome composition as a new risk factor of individual susceptibility to environmental chemicals.” [2013] – likely applies to pharmaceutical chemicals also.
• “The influence of our microbiota reaches from primary metabolites to secondary effects such as substrate competition or the activation of eukaryotic Phase I and Phase II enzymes. Further on it plays a hitherto underestimated role in drug metabolism, toxicity and pathogenesis.” [2015]
• “Metabolism by the intestinal microbiota might result in a different metabolite profile than that produced by host tissues. This could potentially result in either activation or inactivation of the pharmacological and/or toxicological actions of the compound in question. The contribution of the intestinal microbiota to drug metabolism remains relatively unexplored.” [2013]
• ” 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.” [2015]
• A specific example of a bacteria strain that predict cardiac drug metabolism [2017]

Bottom Line for Drug Effectiveness

If a drug has no effect on Monday, it may be effective a week or month later. The cause may be due to diet and/or microbiome (which can be influenced by diet). Welcome to the complexity of human health!

If a drug does not have the desired effect, consider a change of diet, supplements and herbs for 1-2 weeks and then try again.