Grapefruit Juice-Drug Interaction Studies as a Method to Assess the Extent of Intestinal Availability: Utility and Limitations

Abstract

This study aims to assess utility and limitations of grapefruit juice (GFJ) interaction studies as alternative in vivo approach to estimate intestinal availability (F(G)) in comparison to the predominantly used i.v./oral method. The F(G) estimates were obtained from the ratio of AUC in the control and the GFJ group reported previously. Due to large variability in the study design, the following inclusion criteria were applied for the selection of clinical studies: no change in elimination half-life in the presence of GFJ, administration of GFJ with or up to 4 h before drug intake, and a reported significant increase in AUC in the presence of GFJ. Weighted mean F(G) values were compared to estimates from i.v./oral data. Additionally, inter-study and inter-individual variation of GFJ F(G) estimates was assessed by meta-analysis for drugs with multiple studies reported. F(G) values ranged from 0.07 to 0.92 for lovastatin and quinidine, respectively. Overall, the inter-individual variation in GFJ F(G) estimates (16-54%) was higher than the inter-study (5.7-39%) with the exception of nisoldipine and simvastatin where inter-study variations of 53-88% were observed. Weighted average GFJ F(G) estimates were comparable to i.v./oral, supporting the application of this approach as an alternative to i.v./oral data for predominantly metabolised drugs (r(2) = 0.65; n=10). In contrast, this approach is of limited use for drugs whose disposition is co-dependent on efflux/uptake transporters and metabolic enzymes. An area of high intestinal extraction (F(G) < or = 0.25) is identified as problematic, as availability of conclusive data is limited in this area.

Prediction of Human Intestinal First-Pass Metabolism of 25 CYP3A Substrates from In Vitro Clearance and Permeability Data

“…Furthermore, for both drugs CL h approaches Q h , which impedes accurate estimation of in vivo F G , bearing in mind that this parameter is indirectly assessed from intravenous/oral data. Indeed, whereas intravenous/oral data for atorvastatin suggested an F G value of 0.24, grapefruit juice (GFJ) interaction data suggested a less extensive intestinal contribution to atorvastatin first-pass metabolism: F G, GFJ ϭ 0.56 (Gertz et al, 2008a). In the case of tacrolimus, F G predictions were highly variable among the different microsomal pools used within this study, showing a general overprediction trend.…”

“…3 (Yang et al, 2007). F G predictions from the Q Gut model were compared with in vivo F G estimates obtained either from intravenous/oral or grapefruit interaction data (Galetin et al, 2008;Gertz et al, 2008a) and are summarized in Table 5. For indinavir, the F G value was estimated from intravenous/oral data reported by Yeh et al (1999).…”

“…Although the total amount of CYP3A expressed in the human small intestine represents approximately 1% of the hepatic estimate (Paine et al, 1997), considerable drug extraction occurs during absorption of orally administered drugs (Hall et al, 1999;Galetin et al, 2008;Gertz et al, 2008a). This is due to the relatively high enterocytic drug concentration and the considerably lower blood flow to the intestine in comparison to the liver that allows prolonged exposure to the intestinal metabolizing enzymes.…”

“…Two indirect methods have been proposed to estimate F G in vivo, namely use of plasma concentration-time profiles after either oral and intravenous administration or in the presence and absence of grapefruit juice. Both methods have several assumptions that may lead to potential bias in the F G estimates (Galetin et al, 2008;Gertz et al, 2008a).…”

Oral Absorption, Intestinal Metabolism and Human Oral Bioavailability

“…Early studies in liver transplant patients during the anhepatic phase indicated the relative importance of the gut extraction to the first-pass metabolism for drugs such as midazolam and cyclosporine (Paine et al 1996). Further clinical evidences were obtained in the grapefruit juice interaction studies, where coadministration of grape-fruit juice result in the inhibition of gut CYP3A4 without significantly affecting the hepatic metabolism of drugs like felodipine (Gertz et al 2008). However, assessment of the quantitative contribution of intestinal and hepatic extraction in first-pass metabolism is limited by ethical and technical challenges.…”