Wilbur W. Widmer

The effect of grapefruit juice on drug disposition

Introduction: Since their initial discovery in 1989, grapefruit juice (GFJ)–drug interactions have received extensive interest from the scientific, medical, regulatory and lay communities. Although knowledge regarding the effects of GFJ on drug disposition continues to expand, the list of drugs studied in the clinical setting remains relatively limited. Areas covered: This article reviews the in vitro effects of GFJ and its constituents on the activity of CYP enzymes, organic anion-transporting polypeptides (OATPs), P-glycoprotein, esterases and sulfotransferases. The translational applicability of the in vitro findings to the clinical setting is discussed for each drug metabolizing enzyme and transporter. Reported AUC ratios for available GFJ–drug interaction studies are also provided. Relevant investigations were identified by searching the PubMed electronic database from 1989 to 2010. Expert opinion: GFJ increases the bioavailability of some orally administered drugs that are metabolized by CYP3A and normally undergo extensive presystemic extraction. In addition, GFJ can decrease the oral absorption of a few drugs that rely on OATPs in the gastrointestinal tract for their uptake. The number of drugs shown to interact with GFJ in vitro is far greater than the number of clinically relevant GFJ–drug interactions. For the majority of patients, complete avoidance of GFJ is unwarranted.

A Modified Grapefruit Juice Eliminates Two Compound Classes as Major Mediators of the Grapefruit Juice-Fexofenadine Interaction: an In Vitro-In Vivo ‘Connect’

The grapefruit juice (GFJ)–fexofenadine interaction involves inhibition of intestinal organic anion transporting polypeptide (OATP)‐mediated uptake. Only naringin has been shown clinically to inhibit intestinal OATP; other constituents have not been evaluated. The effects of a modified GFJ devoid of furanocoumarins (∼99%) and polymethoxyflavones (∼90%) on fexofenadine disposition were compared to effects of the original juice. Extracts of both juices inhibited estrone 3‐sulfate and fexofenadine uptake by similar extents in OATP‐transfected cells (∼50% and ∼25%, respectively). Healthy volunteers (n = 18) were administered fexofenadine (120 mg) with water, GFJ, or modified GFJ (240 mL) by randomized, three‐way crossover design. Compared to water, both juices decreased fexofenadine geometric mean AUC and Cmax by ∼25% (P ≤ .008 and P ≤ .011, respectively), with no effect on terminal half‐life (P = .11). Similar effects by both juices on fexofenadine pharmacokinetics indicate furanocoumarins and polymethoxyflavones are not major mediators of the GFJ–fexofenadine interaction.

Effect of d-limonene on the Fermentation of Citrus Peel Waste

Approximately 10 million tons of oranges are processed in the US each year, producing approximately 5 million tons of citrus peel waste consisting of peel, seeds and segment membranes. Conversion of citrus peel waste into more valuable products, such as fuel ethanol, would greatly benefit the citrus industry. One of the problems in fermenting sugars in citrus processing waste is the presence of peel oil, which predominantly consists of the antimicrobial terpene d-limonene. This study assessed the tolerance of Saccharomyces cerevisiae to limonene during fermentation of hydrolyzed citrus peel waste. Orange peel waste from a commercial facility was hydrolyzed by commercial pectinase, cellulase, and beta-glucosidae enzymes in 250 ml bottles. Peel oil containing 95% limonene was added back to deoiled citrus waste to give test citrus peel waste with limonene concentrations ranging from 0.08-0.43% (v/w). The peel was hydrolyzed, S. cerevisiae added to the bottles, and the bottles rotated at 10-12 rpm for 24 h at 37 °C under anaerobic conditions. Limonene concentration was measured before and after fermentation and ethanol concentration was measured after fermentation. Ethanol production was inhibited when initial limonene concentration was greater than 0.28% and when limonene concentration after fermentation was greater than 0.12%. Between 38% and 60% of the limonene present before fermentation was removed during fermentation.

Enzymatic Hydrolysis of Grapefruit Peel to Produce Ethanol and Other Products

Over 1 million tons of grapefruit were processed in 2003/04 resulting in 500,000 tons of peel waste. Grapefruit peel waste is usually dried, pelletized, and sold as a low-value cattle feed. This study tested several different loadings of commercial cellulase and pectinase enzymes to hydrolyze grapefruit peel to produce sugars that can be fermented into ethanol and other products. Pectinase and cellulase loadings of zero, one, two, five, and ten mg protein/g peel dry matter were tested. All hydrolyses were supplemented with 2.1 mg beta-glucosidase protein/g peel dry matter to hydrolyze cellobiose produced by cellulase and pectinase. Five mg pectinase/g peel dry matter and one mg cellulase/g peel dry matter were the lowest loadings to yield the most total sugars. Theoretical ethanol yields for grapefruit peel were lower than previous studies utilizing orange peel due to less dry matter in grapefruit peel than in orange peel.

Physical Properties of Fermented Citrus Peel

Each year, the Florida citrus juice industry produces about 3.5~5.0 million tons of wet peel waste, which are currently dried and sold as cattle feed, often at a loss, to dispose of the waste residual. Profitability would be greatly improved if the peel waste could be used to produce higher value products. Previous research has shown that citrus peels can be fermented to produce ethanol with limonene and citrus pectin fragments obtained as co-products. In order to economically strip off the ethanol and develop pectin-based biosorbents using fermented citrus peels, it is essential to understand the physical properties of fermented citrus peels, such as viscosity, solubility, specific heat and heat transfer coefficient. In this study, heat transfer coefficient and specific heat of fermented citrus peels were measured under forced convection using a heat exchanger. The specific heat and heat transfer coefficient were calculated based on steady state convective heat transfer from heating water to fermented peels. The calculated specific heat was 2.56 J kg-1K-1, much lower than that of unfermented peel (3.77 J kg-1K-1). The calculated heat transfer coefficient was 336 Wm-2K-1 at 70 oC, much higher than the value predicted by a laminar flow model. Due to its high viscosity, the flow of fermented peel in a narrow pipe (2.54 cm diameter) is plug flow. The trapped CO2 in the fermented peel could improve vertical mixing, resulting in a much higher heat transfer coefficient. These results would be applicable in the design and optimization of a process for making ethanol from citrus peel waste.