The Experts below are selected from a list of 3510 Experts worldwide ranked by ideXlab platform
Mary F Paine - One of the best experts on this subject based on the ideXlab platform.
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Assessment of a Candidate Marker Constituent Predictive of a Dietary Substance-Drug Interaction: Case Study with Grapefruit Juice and CYP3A4 Drug Substrates
The Journal of pharmacology and experimental therapeutics, 2014Co-Authors: Garrett R. Ainslie, Kristina K. Wolf, Elizabeth A. Connolly, Yolanda Scarlett, J. Heyward Hull, Mary F PaineAbstract:Dietary Substances, including herbal products and citrus juices, can perpetrate interactions with conventional medications. Regulatory guidances for Dietary Substance–drug interaction assessment are lacking. This deficiency is due in part to challenges unique to Dietary Substances, a lack of requisite human-derived data, and limited jurisdiction. An in vitro–in vivo extrapolation (IVIVE) approach to help address some of these hurdles was evaluated using the exemplar Dietary Substance grapefruit juice (GFJ), the candidate marker constituent 6′,7′-dihydroxybergamottin (DHB), and the purported victim drug loperamide. First, the GFJ-loperamide interaction was assessed in 16 healthy volunteers. Loperamide (16 mg) was administered with 240 ml of water or GFJ; plasma was collected from 0 to 72 hours. Relative to water, GFJ increased the geometric mean loperamide area under the plasma concentration–time curve (AUC) significantly (1.7-fold). Second, the mechanism-based inhibition kinetics for DHB were recovered using human intestinal microsomes and the index CYP3A4 reaction, loperamide N-desmethylation (KI [concentration needed to achieve one-half kinact], 5.0 ± 0.9 µM; kinact [maximum inactivation rate constant], 0.38 ± 0.02 minute−1). These parameters were incorporated into a mechanistic static model, which predicted a 1.6-fold increase in loperamide AUC. Third, the successful IVIVE prompted further application to 15 previously reported GFJ-drug interaction studies selected according to predefined criteria. Twelve of the interactions were predicted to within the 25% predefined criterion. Results suggest that DHB could be used to predict the CYP3A4-mediated effect of GFJ. This time- and cost-effective IVIVE approach could be applied to other Dietary Substance–drug interactions to help prioritize new and existing drugs for more advanced (dynamic) modeling and simulation and clinical assessment.
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Identification of Diet-Derived Constituents as Potent Inhibitors of Intestinal Glucuronidation
Drug metabolism and disposition: the biological fate of chemicals, 2014Co-Authors: Brandon T. Gufford, Tyler N. Graf, Nicholas H Oberlies, Gang Chen, Philip Lazarus, Mary F PaineAbstract:Drug-metabolizing enzymes within enterocytes constitute a key barrier to xenobiotic entry into the systemic circulation. Furanocoumarins in grapefruit juice are cornerstone examples of diet-derived xenobiotics that perpetrate interactions with drugs via mechanism-based inhibition of intestinal CYP3A4. Relative to intestinal CYP3A4-mediated inhibition, alternate mechanisms underlying Dietary Substance–drug interactions remain understudied. A working systematic framework was applied to a panel of structurally diverse diet-derived constituents/extracts (n = 15) as inhibitors of intestinal UDP-glucuronosyl transferases (UGTs) to identify and characterize additional perpetrators of Dietary Substance–drug interactions. Using a screening assay involving the nonspecific UGT probe substrate 4-methylumbelliferone, human intestinal microsomes, and human embryonic kidney cell lysates overexpressing gut-relevant UGT1A isoforms, 14 diet-derived constituents/extracts inhibited UGT activity by >50% in at least one enzyme source, prompting IC50 determination. The IC50 values of 13 constituents/extracts (≤10 μM with at least one enzyme source) were well below intestinal tissue concentrations or concentrations in relevant juices, suggesting that these diet-derived Substances can inhibit intestinal UGTs at clinically achievable concentrations. Evaluation of the effect of inhibitor depletion on IC50 determination demonstrated substantial impact (up to 2.8-fold shift) using silybin A and silybin B, two key flavonolignans from milk thistle (Silybum marianum) as exemplar inhibitors, highlighting an important consideration for interpretation of UGT inhibition in vitro. Results from this work will help refine a working systematic framework to identify Dietary Substance–drug interactions that warrant advanced modeling and simulation to inform clinical assessment.
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Mechanisms Underlying Food-Drug Interactions: Inhibition of Intestinal Metabolism and Transport
Pharmacology & therapeutics, 2012Co-Authors: Christina S. Won, Nicholas H Oberlies, Mary F PaineAbstract:Food–drug interaction studies are critical to evaluate appropriate dosing, timing, and formulation of new drug candidates. These interactions often reflect prandial-associated changes in the extent and/or rate of systemic drug exposure. Physiologic and physicochemical mechanisms underlying food effects on drug disposition are well-characterized. However, biochemical mechanisms involving drug metabolizing enzymes and transport proteins remain underexplored. Several plant-derived beverages have been shown to modulate enzymes and transporters in the intestine, leading to altered pharmacokinetic (PK) and potentially negative pharmacodynamic (PD) outcomes. Commonly consumed fruit juices, teas, and alcoholic drinks contain phytochemicals that inhibit intestinal cytochrome P450 and phase II conjugation enzymes, as well as uptake and efflux transport proteins. Whereas myriad phytochemicals have been shown to inhibit these processes in vitro, translation to the clinic has been deemed insignificant or undetermined. An overlooked prerequisite for elucidating food effects on drug PK is thorough knowledge of causative bioactive ingredients. Substantial variability in bioactive ingredient composition and activity of a given Dietary Substance poses a challenge in conducting robust food–drug interaction studies. This confounding factor can be addressed by identifying and characterizing specific components, which could be used as marker compounds to improve clinical trial design and quantitatively predict food effects. Interpretation and integration of data from in vitro, in vivo, and in silico studies require collaborative expertise from multiple disciplines, from botany to clinical pharmacology (i.e., plant to patient). Development of more systematic methods and guidelines is needed to address the general lack of information on examining drug–Dietary Substance interactions prospectively.
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Influence of Dietary Substances on Intestinal Drug Metabolism and Transport
Current drug metabolism, 2010Co-Authors: Christina S. Won, Nicholas H Oberlies, Mary F PaineAbstract:Successful delivery of promising new chemical entities via the oral route is rife with challenges, some of which cannot be explained or foreseen during drug development. Further complicating an already multifaceted problem is the obvious, yet often overlooked, effect of Dietary Substances on drug disposition and response. Some Dietary Substances, particularly fruit juices, have been shown to inhibit biochemical processes in the intestine, leading to altered pharmacokinetic (PK), and potentially pharmacodynamic (PD), outcomes. Inhibition of intestinal CYP3A-mediated metabolism is the major mechanism by which fruit juices, including grapefruit juice, enhances systemic exposure to new and already marketed drugs. Inhibition of intestinal non-CYP3A enzymes and apically-located transport proteins represent recently identified mechanisms that can alter PK and PD. Several fruit juices have been shown to inhibit these processes in vitro, but some interactions have not translated to the clinic. The lack of in vitro-in vivo concordance is due largely to a lack of rigorous methods to elucidate causative ingredients prior to clinical testing. Identification of specific components and underlying mechanisms is challenging, as Dietary Substances frequently contain multiple, often unknown, bioactive ingredients that vary in composition and bioactivity. A translational research approach, combining expertise from clinical pharmacologists and natural products chemists, is needed to develop robust models describing PK/PD relationships between a given Dietary Substance and drug of interest. Validation of these models through well-designed clinical trials would facilitate development of common practice guidelines for managing drug-Dietary Substance interactions appropriately.
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Isolation and Identification of Intestinal CYP3A Inhibitors from Cranberry (Vaccinium macrocarpon) using Human Intestinal Microsomes
Planta Medica, 2010Co-Authors: Eun-kyung Kim, Tyler N. Graf, Mary F Paine, Arlene A. Sy-cordero, Scott J. Brantley, Nicholas H OberliesAbstract:Cranberry juice is used routinely, especially among women and the elderly, to prevent and treat urinary tract infections. These individuals are likely to be taking medications concomitantly with cranberry juice, leading to concern about potential drug-Dietary Substance interactions, particularly in the intestine, which, along with the liver, is rich in expression of the prominent drug metabolizing enzyme, cytochrome P450 3A (CYP3A). Using a systematic in vitro-in vivo approach, a cranberry juice product was identified recently that elicited a pharmacokinetic interaction with the CYP3A probe substrate midazolam in 16 healthy volunteers. Relative to water, cranberry juice inhibited intestinal first-pass midazolam metabolism. In vitro studies were initiated to identify potential enteric CYP3A inhibitors from cranberry via a bioactivity-directed fractionation approach involving dried whole cranberry [Vaccinium macrocarpon Ait. (Ericaceae)], midazolam, and human intestinal microsomes (HIM). Three triterpenes (maslinic acid, corosolic acid, and ursolic acid) were isolated. The inhibitory potency (IC(50)) of maslinic acid, corosolic acid, and ursolic acid was 7.4, 8.8, and < 10 µM, respectively, using HIM as the enzyme source and 2.8, 4.3, and < 10 µM, respectively, using recombinant CYP3A4 as the enzyme source. These in vitro inhibitory potencies, which are within the range of those reported for two CYP3A inhibitory components in grapefruit juice, suggest that these triterpenes may have contributed to the midazolam-cranberry juice interaction observed in the clinical study.
Nicholas H Oberlies - One of the best experts on this subject based on the ideXlab platform.
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Identification of Diet-Derived Constituents as Potent Inhibitors of Intestinal Glucuronidation
Drug metabolism and disposition: the biological fate of chemicals, 2014Co-Authors: Brandon T. Gufford, Tyler N. Graf, Nicholas H Oberlies, Gang Chen, Philip Lazarus, Mary F PaineAbstract:Drug-metabolizing enzymes within enterocytes constitute a key barrier to xenobiotic entry into the systemic circulation. Furanocoumarins in grapefruit juice are cornerstone examples of diet-derived xenobiotics that perpetrate interactions with drugs via mechanism-based inhibition of intestinal CYP3A4. Relative to intestinal CYP3A4-mediated inhibition, alternate mechanisms underlying Dietary Substance–drug interactions remain understudied. A working systematic framework was applied to a panel of structurally diverse diet-derived constituents/extracts (n = 15) as inhibitors of intestinal UDP-glucuronosyl transferases (UGTs) to identify and characterize additional perpetrators of Dietary Substance–drug interactions. Using a screening assay involving the nonspecific UGT probe substrate 4-methylumbelliferone, human intestinal microsomes, and human embryonic kidney cell lysates overexpressing gut-relevant UGT1A isoforms, 14 diet-derived constituents/extracts inhibited UGT activity by >50% in at least one enzyme source, prompting IC50 determination. The IC50 values of 13 constituents/extracts (≤10 μM with at least one enzyme source) were well below intestinal tissue concentrations or concentrations in relevant juices, suggesting that these diet-derived Substances can inhibit intestinal UGTs at clinically achievable concentrations. Evaluation of the effect of inhibitor depletion on IC50 determination demonstrated substantial impact (up to 2.8-fold shift) using silybin A and silybin B, two key flavonolignans from milk thistle (Silybum marianum) as exemplar inhibitors, highlighting an important consideration for interpretation of UGT inhibition in vitro. Results from this work will help refine a working systematic framework to identify Dietary Substance–drug interactions that warrant advanced modeling and simulation to inform clinical assessment.
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Mechanisms Underlying Food-Drug Interactions: Inhibition of Intestinal Metabolism and Transport
Pharmacology & therapeutics, 2012Co-Authors: Christina S. Won, Nicholas H Oberlies, Mary F PaineAbstract:Food–drug interaction studies are critical to evaluate appropriate dosing, timing, and formulation of new drug candidates. These interactions often reflect prandial-associated changes in the extent and/or rate of systemic drug exposure. Physiologic and physicochemical mechanisms underlying food effects on drug disposition are well-characterized. However, biochemical mechanisms involving drug metabolizing enzymes and transport proteins remain underexplored. Several plant-derived beverages have been shown to modulate enzymes and transporters in the intestine, leading to altered pharmacokinetic (PK) and potentially negative pharmacodynamic (PD) outcomes. Commonly consumed fruit juices, teas, and alcoholic drinks contain phytochemicals that inhibit intestinal cytochrome P450 and phase II conjugation enzymes, as well as uptake and efflux transport proteins. Whereas myriad phytochemicals have been shown to inhibit these processes in vitro, translation to the clinic has been deemed insignificant or undetermined. An overlooked prerequisite for elucidating food effects on drug PK is thorough knowledge of causative bioactive ingredients. Substantial variability in bioactive ingredient composition and activity of a given Dietary Substance poses a challenge in conducting robust food–drug interaction studies. This confounding factor can be addressed by identifying and characterizing specific components, which could be used as marker compounds to improve clinical trial design and quantitatively predict food effects. Interpretation and integration of data from in vitro, in vivo, and in silico studies require collaborative expertise from multiple disciplines, from botany to clinical pharmacology (i.e., plant to patient). Development of more systematic methods and guidelines is needed to address the general lack of information on examining drug–Dietary Substance interactions prospectively.
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Influence of Dietary Substances on Intestinal Drug Metabolism and Transport
Current drug metabolism, 2010Co-Authors: Christina S. Won, Nicholas H Oberlies, Mary F PaineAbstract:Successful delivery of promising new chemical entities via the oral route is rife with challenges, some of which cannot be explained or foreseen during drug development. Further complicating an already multifaceted problem is the obvious, yet often overlooked, effect of Dietary Substances on drug disposition and response. Some Dietary Substances, particularly fruit juices, have been shown to inhibit biochemical processes in the intestine, leading to altered pharmacokinetic (PK), and potentially pharmacodynamic (PD), outcomes. Inhibition of intestinal CYP3A-mediated metabolism is the major mechanism by which fruit juices, including grapefruit juice, enhances systemic exposure to new and already marketed drugs. Inhibition of intestinal non-CYP3A enzymes and apically-located transport proteins represent recently identified mechanisms that can alter PK and PD. Several fruit juices have been shown to inhibit these processes in vitro, but some interactions have not translated to the clinic. The lack of in vitro-in vivo concordance is due largely to a lack of rigorous methods to elucidate causative ingredients prior to clinical testing. Identification of specific components and underlying mechanisms is challenging, as Dietary Substances frequently contain multiple, often unknown, bioactive ingredients that vary in composition and bioactivity. A translational research approach, combining expertise from clinical pharmacologists and natural products chemists, is needed to develop robust models describing PK/PD relationships between a given Dietary Substance and drug of interest. Validation of these models through well-designed clinical trials would facilitate development of common practice guidelines for managing drug-Dietary Substance interactions appropriately.
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Isolation and Identification of Intestinal CYP3A Inhibitors from Cranberry (Vaccinium macrocarpon) using Human Intestinal Microsomes
Planta Medica, 2010Co-Authors: Eun-kyung Kim, Tyler N. Graf, Mary F Paine, Arlene A. Sy-cordero, Scott J. Brantley, Nicholas H OberliesAbstract:Cranberry juice is used routinely, especially among women and the elderly, to prevent and treat urinary tract infections. These individuals are likely to be taking medications concomitantly with cranberry juice, leading to concern about potential drug-Dietary Substance interactions, particularly in the intestine, which, along with the liver, is rich in expression of the prominent drug metabolizing enzyme, cytochrome P450 3A (CYP3A). Using a systematic in vitro-in vivo approach, a cranberry juice product was identified recently that elicited a pharmacokinetic interaction with the CYP3A probe substrate midazolam in 16 healthy volunteers. Relative to water, cranberry juice inhibited intestinal first-pass midazolam metabolism. In vitro studies were initiated to identify potential enteric CYP3A inhibitors from cranberry via a bioactivity-directed fractionation approach involving dried whole cranberry [Vaccinium macrocarpon Ait. (Ericaceae)], midazolam, and human intestinal microsomes (HIM). Three triterpenes (maslinic acid, corosolic acid, and ursolic acid) were isolated. The inhibitory potency (IC(50)) of maslinic acid, corosolic acid, and ursolic acid was 7.4, 8.8, and < 10 µM, respectively, using HIM as the enzyme source and 2.8, 4.3, and < 10 µM, respectively, using recombinant CYP3A4 as the enzyme source. These in vitro inhibitory potencies, which are within the range of those reported for two CYP3A inhibitory components in grapefruit juice, suggest that these triterpenes may have contributed to the midazolam-cranberry juice interaction observed in the clinical study.
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identification of a cranberry juice product that inhibits enteric cyp3a mediated first pass metabolism in humans
Drug Metabolism and Disposition, 2009Co-Authors: Tyler N. Graf, Daniel R Carrizosa, Claire E Dees, Angela D M Kashuba, Nicholas H Oberlies, Mary F PaineAbstract:Cranberry juice has become popular as a natural alternative for the prevention of urinary tract infections (UTIs), which have a high incidence in women and elderly persons (Foxman, 2003; McMurdo et al., 2005; Jepson and Craig, 2008). Moreover, cranberry juice has shown efficacy in reducing UTIs in women with recurrent episodes and in reducing bacteriuria in elderly persons (Avorn et al., 1994; Stothers, 2002). Clinical benefits are associated with chronic use (months) and with a regular frequency of consumption (daily) (Jepson and Craig, 2008). Studies have shown that the prophylactic nature of cranberry juice is a result of inhibition of the adhesion of bacterial fimbriae to uroepithelial cells, rather than because of urinary acidification (Liu et al., 2006; Gupta et al., 2007). Cranberry juice also has shown a beneficial effect against drug-resistant bacteria (Howell and Foxman, 2002), which could be important in institutional settings, where nosocomial infections are frequent. Despite these seemingly beneficial attributes, studies have suggested that cranberry juice may be capable of eliciting clinically relevant interactions with certain medications, albeit the literature is inconsistent. For example, in rats, cranberry juice was as effective as grapefruit juice in enhancing the systemic exposure of the calcium channel antagonist and cytochrome P450 3A (CYP3A) substrate nifedipine (Uesawa and Mohri, 2006). Compared with saline, both grapefruit juice and cranberry juice significantly increased the area under the curve (AUC) of nifedipine by 60%. Moreover, similar to grapefruit juice, cranberry juice seemed to inhibit enteric, but not hepatic, CYP3A-mediated first-pass metabolism, as exemplified by the lack of effect on drug systemic half-life. In contrast, a human study involving the CYP3A substrate cyclosporine and cranberry juice indicated no interaction (Grenier et al., 2006). However, cyclosporine is also a substrate for the enteric efflux transporter P-glycoprotein (P-gp), which complicates the interpretation of whether cranberry juice inhibits enteric CYP3A. In addition, only a single glass (240 ml) of juice was given, which conflicts with the general recommendation of consuming several glasses daily for the prevention of UTIs (Lynch, 2004). Most recently, Lilja et al. (2007) reported that cranberry juice, taken thrice daily for 10 days, had no effect on the pharmacokinetics of the CYP3A probe substrate midazolam, which was administered as a single oral dose on day 5. Although a more appropriate probe substrate and real-life scenario of long-term exposure was examined, some comments warrant mention. In particular, no rationale was provided as to why cranberry juice was taken for 10 days, why midazolam was given on day 5, or why a sample size of 10 was chosen. Nevertheless, the current literature suggests that cranberry juice has a drug interaction liability for rats, but not humans, and thus has no clinical concerns. An oversight to the aforementioned conclusion is that each study examined a single brand of juice, which, like all products derived from natural Substances, vary considerably in the composition of bioactive ingredients (Paine and Oberlies, 2007). Accordingly, an alternate conclusion is that the product tested in the rat study contained a suite of CYP3A inhibitory compounds at an aggregate concentration sufficient to elicit an inhibitory effect in vivo, whereas the products used in the clinical studies did not. However, this supposition is not easily assessable because none of the authors reported an in vitro characterization of the test juice with respect to enteric CYP3A inhibitory activity before initiation of the in vivo study. Because such a priori testing is required for evaluation of the metabolic consequence of new chemical entities, it follows that similar procedures should be implemented for evaluation of the effects of Dietary Substances on drug disposition (Paine and Oberlies, 2007). Based on the inconsistencies in the literature regarding a potential cranberry juice effect, along with the challenges that present when evaluating the drug interaction liability of a Dietary Substance, cranberry juice was selected as a model Substance to test the hypothesis that a systematic approach should be used to identify clinically relevant drug-diet interactions prospectively. First, multiple cranberry juice products were tested as inhibitors of enteric CYP3A activity using midazolam and human intestinal microsomes. Second, the most potent juice was fractionated using established natural products chemistry techniques, and the resultant fractions were tested as inhibitors of enteric CYP3A activity. Third, the physicochemical effects of the selected test juice on the absorption of midazolam were evaluated using the human intestinal cell line Caco-2. Finally, the test juice was evaluated on the oral pharmacokinetics of midazolam in healthy volunteers. This approach identified a cranberry juice that elicited a pharmacokinetic interaction with an established CYP3A probe substrate, substantiating that a rigorous in vitro characterization of a Dietary Substance should be undertaken before initiation of a clinical drug-diet interaction study. These observations also raise concerns for individuals taking certain medications concomitantly with certain brands of cranberry juice.
Jennifer Grebow - One of the best experts on this subject based on the ideXlab platform.
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Will FDA change its definition of a Dietary ingredient
2019Co-Authors: Jennifer GrebowAbstract:The definition of a Dietary Substance in FDA's New Dietary Ingredient draft guidance differs greatly from the definition of a Dietary ingredient under DSHEA, the actual law governing supplements.
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DSHEA Expert Says FDA’s “Misreading” of the Term “Dietary Substance” in NDI Draft Guidance Is Biggest Hurdle for Synthetic Botanicals, Probiotics
2017Co-Authors: Jennifer GrebowAbstract:Attorney Scott Bass, who helped draft the DSHEA law of 1994, says that Congress did not intend “Dietary Substances” only to be limited to ingredients that are nutritional—and that this should mean that synthetic botanicals and probiotics count as Dietary ingredients and be eligible for use in Dietary supplements.
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dshea expert says fda s misreading of the term Dietary Substance in ndi draft guidance is biggest hurdle for synthetic botanicals probiotics
2017Co-Authors: Jennifer GrebowAbstract:Attorney Scott Bass, who helped draft the DSHEA law of 1994, says that Congress did not intend “Dietary Substances” only to be limited to ingredients that are nutritional—and that this should mean that synthetic botanicals and probiotics count as Dietary ingredients and be eligible for use in Dietary supplements.
Christina S. Won - One of the best experts on this subject based on the ideXlab platform.
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Mechanisms Underlying Food-Drug Interactions: Inhibition of Intestinal Metabolism and Transport
Pharmacology & therapeutics, 2012Co-Authors: Christina S. Won, Nicholas H Oberlies, Mary F PaineAbstract:Food–drug interaction studies are critical to evaluate appropriate dosing, timing, and formulation of new drug candidates. These interactions often reflect prandial-associated changes in the extent and/or rate of systemic drug exposure. Physiologic and physicochemical mechanisms underlying food effects on drug disposition are well-characterized. However, biochemical mechanisms involving drug metabolizing enzymes and transport proteins remain underexplored. Several plant-derived beverages have been shown to modulate enzymes and transporters in the intestine, leading to altered pharmacokinetic (PK) and potentially negative pharmacodynamic (PD) outcomes. Commonly consumed fruit juices, teas, and alcoholic drinks contain phytochemicals that inhibit intestinal cytochrome P450 and phase II conjugation enzymes, as well as uptake and efflux transport proteins. Whereas myriad phytochemicals have been shown to inhibit these processes in vitro, translation to the clinic has been deemed insignificant or undetermined. An overlooked prerequisite for elucidating food effects on drug PK is thorough knowledge of causative bioactive ingredients. Substantial variability in bioactive ingredient composition and activity of a given Dietary Substance poses a challenge in conducting robust food–drug interaction studies. This confounding factor can be addressed by identifying and characterizing specific components, which could be used as marker compounds to improve clinical trial design and quantitatively predict food effects. Interpretation and integration of data from in vitro, in vivo, and in silico studies require collaborative expertise from multiple disciplines, from botany to clinical pharmacology (i.e., plant to patient). Development of more systematic methods and guidelines is needed to address the general lack of information on examining drug–Dietary Substance interactions prospectively.
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Influence of Dietary Substances on Intestinal Drug Metabolism and Transport
Current drug metabolism, 2010Co-Authors: Christina S. Won, Nicholas H Oberlies, Mary F PaineAbstract:Successful delivery of promising new chemical entities via the oral route is rife with challenges, some of which cannot be explained or foreseen during drug development. Further complicating an already multifaceted problem is the obvious, yet often overlooked, effect of Dietary Substances on drug disposition and response. Some Dietary Substances, particularly fruit juices, have been shown to inhibit biochemical processes in the intestine, leading to altered pharmacokinetic (PK), and potentially pharmacodynamic (PD), outcomes. Inhibition of intestinal CYP3A-mediated metabolism is the major mechanism by which fruit juices, including grapefruit juice, enhances systemic exposure to new and already marketed drugs. Inhibition of intestinal non-CYP3A enzymes and apically-located transport proteins represent recently identified mechanisms that can alter PK and PD. Several fruit juices have been shown to inhibit these processes in vitro, but some interactions have not translated to the clinic. The lack of in vitro-in vivo concordance is due largely to a lack of rigorous methods to elucidate causative ingredients prior to clinical testing. Identification of specific components and underlying mechanisms is challenging, as Dietary Substances frequently contain multiple, often unknown, bioactive ingredients that vary in composition and bioactivity. A translational research approach, combining expertise from clinical pharmacologists and natural products chemists, is needed to develop robust models describing PK/PD relationships between a given Dietary Substance and drug of interest. Validation of these models through well-designed clinical trials would facilitate development of common practice guidelines for managing drug-Dietary Substance interactions appropriately.
Tyler N. Graf - One of the best experts on this subject based on the ideXlab platform.
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Identification of Diet-Derived Constituents as Potent Inhibitors of Intestinal Glucuronidation
Drug metabolism and disposition: the biological fate of chemicals, 2014Co-Authors: Brandon T. Gufford, Tyler N. Graf, Nicholas H Oberlies, Gang Chen, Philip Lazarus, Mary F PaineAbstract:Drug-metabolizing enzymes within enterocytes constitute a key barrier to xenobiotic entry into the systemic circulation. Furanocoumarins in grapefruit juice are cornerstone examples of diet-derived xenobiotics that perpetrate interactions with drugs via mechanism-based inhibition of intestinal CYP3A4. Relative to intestinal CYP3A4-mediated inhibition, alternate mechanisms underlying Dietary Substance–drug interactions remain understudied. A working systematic framework was applied to a panel of structurally diverse diet-derived constituents/extracts (n = 15) as inhibitors of intestinal UDP-glucuronosyl transferases (UGTs) to identify and characterize additional perpetrators of Dietary Substance–drug interactions. Using a screening assay involving the nonspecific UGT probe substrate 4-methylumbelliferone, human intestinal microsomes, and human embryonic kidney cell lysates overexpressing gut-relevant UGT1A isoforms, 14 diet-derived constituents/extracts inhibited UGT activity by >50% in at least one enzyme source, prompting IC50 determination. The IC50 values of 13 constituents/extracts (≤10 μM with at least one enzyme source) were well below intestinal tissue concentrations or concentrations in relevant juices, suggesting that these diet-derived Substances can inhibit intestinal UGTs at clinically achievable concentrations. Evaluation of the effect of inhibitor depletion on IC50 determination demonstrated substantial impact (up to 2.8-fold shift) using silybin A and silybin B, two key flavonolignans from milk thistle (Silybum marianum) as exemplar inhibitors, highlighting an important consideration for interpretation of UGT inhibition in vitro. Results from this work will help refine a working systematic framework to identify Dietary Substance–drug interactions that warrant advanced modeling and simulation to inform clinical assessment.
-
Isolation and Identification of Intestinal CYP3A Inhibitors from Cranberry (Vaccinium macrocarpon) using Human Intestinal Microsomes
Planta Medica, 2010Co-Authors: Eun-kyung Kim, Tyler N. Graf, Mary F Paine, Arlene A. Sy-cordero, Scott J. Brantley, Nicholas H OberliesAbstract:Cranberry juice is used routinely, especially among women and the elderly, to prevent and treat urinary tract infections. These individuals are likely to be taking medications concomitantly with cranberry juice, leading to concern about potential drug-Dietary Substance interactions, particularly in the intestine, which, along with the liver, is rich in expression of the prominent drug metabolizing enzyme, cytochrome P450 3A (CYP3A). Using a systematic in vitro-in vivo approach, a cranberry juice product was identified recently that elicited a pharmacokinetic interaction with the CYP3A probe substrate midazolam in 16 healthy volunteers. Relative to water, cranberry juice inhibited intestinal first-pass midazolam metabolism. In vitro studies were initiated to identify potential enteric CYP3A inhibitors from cranberry via a bioactivity-directed fractionation approach involving dried whole cranberry [Vaccinium macrocarpon Ait. (Ericaceae)], midazolam, and human intestinal microsomes (HIM). Three triterpenes (maslinic acid, corosolic acid, and ursolic acid) were isolated. The inhibitory potency (IC(50)) of maslinic acid, corosolic acid, and ursolic acid was 7.4, 8.8, and < 10 µM, respectively, using HIM as the enzyme source and 2.8, 4.3, and < 10 µM, respectively, using recombinant CYP3A4 as the enzyme source. These in vitro inhibitory potencies, which are within the range of those reported for two CYP3A inhibitory components in grapefruit juice, suggest that these triterpenes may have contributed to the midazolam-cranberry juice interaction observed in the clinical study.
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identification of a cranberry juice product that inhibits enteric cyp3a mediated first pass metabolism in humans
Drug Metabolism and Disposition, 2009Co-Authors: Tyler N. Graf, Daniel R Carrizosa, Claire E Dees, Angela D M Kashuba, Nicholas H Oberlies, Mary F PaineAbstract:Cranberry juice has become popular as a natural alternative for the prevention of urinary tract infections (UTIs), which have a high incidence in women and elderly persons (Foxman, 2003; McMurdo et al., 2005; Jepson and Craig, 2008). Moreover, cranberry juice has shown efficacy in reducing UTIs in women with recurrent episodes and in reducing bacteriuria in elderly persons (Avorn et al., 1994; Stothers, 2002). Clinical benefits are associated with chronic use (months) and with a regular frequency of consumption (daily) (Jepson and Craig, 2008). Studies have shown that the prophylactic nature of cranberry juice is a result of inhibition of the adhesion of bacterial fimbriae to uroepithelial cells, rather than because of urinary acidification (Liu et al., 2006; Gupta et al., 2007). Cranberry juice also has shown a beneficial effect against drug-resistant bacteria (Howell and Foxman, 2002), which could be important in institutional settings, where nosocomial infections are frequent. Despite these seemingly beneficial attributes, studies have suggested that cranberry juice may be capable of eliciting clinically relevant interactions with certain medications, albeit the literature is inconsistent. For example, in rats, cranberry juice was as effective as grapefruit juice in enhancing the systemic exposure of the calcium channel antagonist and cytochrome P450 3A (CYP3A) substrate nifedipine (Uesawa and Mohri, 2006). Compared with saline, both grapefruit juice and cranberry juice significantly increased the area under the curve (AUC) of nifedipine by 60%. Moreover, similar to grapefruit juice, cranberry juice seemed to inhibit enteric, but not hepatic, CYP3A-mediated first-pass metabolism, as exemplified by the lack of effect on drug systemic half-life. In contrast, a human study involving the CYP3A substrate cyclosporine and cranberry juice indicated no interaction (Grenier et al., 2006). However, cyclosporine is also a substrate for the enteric efflux transporter P-glycoprotein (P-gp), which complicates the interpretation of whether cranberry juice inhibits enteric CYP3A. In addition, only a single glass (240 ml) of juice was given, which conflicts with the general recommendation of consuming several glasses daily for the prevention of UTIs (Lynch, 2004). Most recently, Lilja et al. (2007) reported that cranberry juice, taken thrice daily for 10 days, had no effect on the pharmacokinetics of the CYP3A probe substrate midazolam, which was administered as a single oral dose on day 5. Although a more appropriate probe substrate and real-life scenario of long-term exposure was examined, some comments warrant mention. In particular, no rationale was provided as to why cranberry juice was taken for 10 days, why midazolam was given on day 5, or why a sample size of 10 was chosen. Nevertheless, the current literature suggests that cranberry juice has a drug interaction liability for rats, but not humans, and thus has no clinical concerns. An oversight to the aforementioned conclusion is that each study examined a single brand of juice, which, like all products derived from natural Substances, vary considerably in the composition of bioactive ingredients (Paine and Oberlies, 2007). Accordingly, an alternate conclusion is that the product tested in the rat study contained a suite of CYP3A inhibitory compounds at an aggregate concentration sufficient to elicit an inhibitory effect in vivo, whereas the products used in the clinical studies did not. However, this supposition is not easily assessable because none of the authors reported an in vitro characterization of the test juice with respect to enteric CYP3A inhibitory activity before initiation of the in vivo study. Because such a priori testing is required for evaluation of the metabolic consequence of new chemical entities, it follows that similar procedures should be implemented for evaluation of the effects of Dietary Substances on drug disposition (Paine and Oberlies, 2007). Based on the inconsistencies in the literature regarding a potential cranberry juice effect, along with the challenges that present when evaluating the drug interaction liability of a Dietary Substance, cranberry juice was selected as a model Substance to test the hypothesis that a systematic approach should be used to identify clinically relevant drug-diet interactions prospectively. First, multiple cranberry juice products were tested as inhibitors of enteric CYP3A activity using midazolam and human intestinal microsomes. Second, the most potent juice was fractionated using established natural products chemistry techniques, and the resultant fractions were tested as inhibitors of enteric CYP3A activity. Third, the physicochemical effects of the selected test juice on the absorption of midazolam were evaluated using the human intestinal cell line Caco-2. Finally, the test juice was evaluated on the oral pharmacokinetics of midazolam in healthy volunteers. This approach identified a cranberry juice that elicited a pharmacokinetic interaction with an established CYP3A probe substrate, substantiating that a rigorous in vitro characterization of a Dietary Substance should be undertaken before initiation of a clinical drug-diet interaction study. These observations also raise concerns for individuals taking certain medications concomitantly with certain brands of cranberry juice.