Effects of Grapefruit Juice on Intestinal P‐glycoprotein: Evaluation Using Digoxin in Humans

Parker, Robert B.; Yates, Charles R.; Soberman, Judith E.; Laizure, S. Casey

doi:10.1592/phco.23.8.979.32881

Cited by 58 publications

(44 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Digoxin transport has been used intensively as P-gp substrate in vitro, and grapefruit juice reduces digoxin transport in cell culture models. Nevertheless, grapefruit juice has only a minor effect on the pharmacokinetics of digoxin as shown in two studies (Becquemont et al, 2001;Parker et al, 2003), suggesting that the overall effect of grapefruit juice on P-gp-mediated drug transport (at least for digoxin) is limited. Taken together P-gp inhibition by grapefruit juice appears to be of limited clinical significance.…”

Section: Drug-food Interactionsmentioning

confidence: 99%

Transporters and Drug-Drug Interactions: Important Determinants of Drug Disposition and Effects

2013

View full text Add to dashboard Cite

Section: Drug-food Interactionsmentioning

confidence: 99%

Transporters and Drug-Drug Interactions: Important Determinants of Drug Disposition and Effects

2013

View full text Add to dashboard Cite

“…Shi et al further noted that there are other P-gp inhibitor examples such as grapefruit juice and ketoconazole that do not alter the exposure of digoxin. However, although grapefruit juice did not change digoxin exposure, there was a change in the rate of absorption (k a and t lag ) 13 . Also the effect of grapefruit juice on intestinal P-gp will be variable among brands and is known to be dependent on the concentration and the preparation [14][15][16] .…”

mentioning

confidence: 78%

Response from the International Transporter Consortium

Lee

Hillgren

Zhang³

et al. 2010

Nat Rev Drug Discov

View full text Add to dashboard Cite

We are grateful for the comments on our article (Membrane transporters in drug development. Nature Rev. Drug Discov. 9, 215-236 (2010)) 1 from Shi, Zhang and Yeleswaram (The relevance of assessment of intestinal P-gp inhibition using digoxin as an in vivo probe substrate. 31 Dec 2010 (doi:10.1038/nrd3028-c1)) 2 regarding their assessment of the utility of digoxin as an in vivo probe for P-glycoprotein (P-gp). Overall, the International Transporter Consortium (ITC) is in agreement with their comments and supports future research to identify better in vivo probes for P-gp. Below are further thoughts from the ITC on some of the salient points highlighted by Shi and colleagues.Utility of digoxin as an in vivo probe. The ITC Review did highlight (in the "Decision trees for P-glycoprotein or BCRP inhibitor interactions" (Box 3)) a number of the same limitations of digoxin as a clinical probe as those pointed out by Shi and colleagues. For instance, digoxin was noted as a "unique drug" and may not be the best reference for decisions regarding interaction studies with other P-gp substrate drugs. However, owing to its narrow therapeutic index, interactions that alter the area under the curve (AUC) for digoxin ≥ 1.25-fold, whether driven by P-gp, other transporters or solubility enhancement, are clinically important for digoxin, as dose adjustment may be warranted. The ITC advised readers to be cautious and not to over-extrapolate the significance of P-gp drug-drug interactions based on the importance of these findings for digoxin.Further guidance was also given that, if the new molecular entity (NME) is a pure P-gp inhibitor, no drug-drug interaction (DDI) studies may be required other than for clarifying a digoxin dose adjustment requirement, depending on the therapeutic area of the NME and its drug-labelling considerations. It is of crucial importance that the decision to conduct a clinical P-gp DDI study is based on an integration of all the nonclinical and clinical data for the NME. In summary, because digoxin has a narrow therapeutic index and it is a substrate for intestinal P-gp (discussed below), the ITC thinks that clinical DDI studies with drugs that are inhibitors of P-gp should be considered as described in the decision tree.Importance of solubility and formulation on digoxin absorption. The ITC did mention the importance of considering the digoxin formulation to use in the clinical DDI study, as the different formulations of digoxin have different bioavailability values. As pointed out by the ITC and Shi and colleagues, the standard digoxin tablet has an absolute bioavailability of ~70%, whereas bioavailability for the liquid-filled formulation (that is, the Lanoxicaps capsule) is ~90%. It is of note that the Lanoxicaps capsule product has not been commercially available in the US market since March 2008 (REF. 3); the formal withdrawal due to commercial reasons was requested in July 2010.Shi and colleagues present an interesting position that a clinical interaction study with digoxin should be mandatory fo...

show abstract

“…7,8) For example, it is well known that St. John's wort influences P-glycoprotein. 9,10) However, it is not clear whether a lot of foods, except some foods (e.g., quercetin, 10) grapefruit juice, [11][12][13] pomelo juice 14) ), are able to influence P-glycoprotein. This new assay using a confocal laser microscopic image analyzer will contribute to generating an extensive database of valuable information on potential P-glycoprotein-related interactions between drugs, drug candidates and food ingredients.…”

Section: Discussionmentioning

confidence: 99%

Highly Sensitive Measurement of P-Glycoprotein-Mediated Transport Activity in Caco-2 Cells

Wakuda

Nejime

Tada

et al. 2010

Biological & Pharmaceutical Bulletin

View full text Add to dashboard Cite

Effects of Grapefruit Juice on Intestinal P‐glycoprotein: Evaluation Using Digoxin in Humans

Abstract: Inhibition of intestinal P-glycoprotein does not appear to play an important role in drug interactions involving grapefruit juice. Interindividual variability in response to grapefruit juice may be related to the balance of intestinal drug uptake and efflux transport.

Cited by 58 publications

References 48 publications

Transporters and Drug-Drug Interactions: Important Determinants of Drug Disposition and Effects

Transporters and Drug-Drug Interactions: Important Determinants of Drug Disposition and Effects

Response from the International Transporter Consortium

Highly Sensitive Measurement of P-Glycoprotein-Mediated Transport Activity in Caco-2 Cells

Contact Info

Product

Resources

About