Predicting Inhibitory Drug—Drug Interactions and Evaluating Drug Interaction           Reports Using Inhibition Constants

Bachmann, Kenneth; Lewis, Jeffrey D.

doi:10.1345/aph.1e508

Cited by 91 publications

(56 citation statements)

References 23 publications

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“…The unbound concentration of an inhibitor is usually applied in this respect. However, it has been suggested that, at least for metabolic interactions, it may be more appropriate to use the total concentration in these calculations (Ito et al, 2004;Bachmann and Lewis, 2005). In this study, estimates based on total CsA concentrations show that the degree of OATP1B1 PS int inhibition would be more than 94% throughout the dosing interval, with a maximum of 99% (Fig.…”

Section: Cyclosporine a But Not Tacrolimus Inhibits Oatp1b1mentioning

confidence: 74%

Cyclosporine A, but Not Tacrolimus, Shows Relevant Inhibition of Organic Anion-Transporting Protein 1B1-Mediated Transport of Atorvastatin

Amundsen¹,

Christensen²,

Zabihyan³

et al. 2010

Drug Metab Dispos

126

107

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ABSTRACT:The aim of this study was to investigate the potential of calcineurin inhibitors [cyclosporine A (CsA) and tacrolimus (Tac)] to inhibit cellular uptake of atorvastatin mediated by the liver-specific organic anion-transporting polypeptide 1B1 ( The IVIVE showed that clinically obtainable concentrations of CsA, but not Tac, inhibit OATP1B1 transport of atorvastatin. CsA inhibition ranged from 28 to 77% within a dosing interval, whereas it was less than 1% for Tac, considering free concentrations and assuming competitive inhibition. This does not fully explain the clinically observed interaction with CsA, suggesting that a more complex inhibitory mechanism may be present. This is also supported by the decreased IC 50 value of CsA after preincubation. This study provides evidence that OATP1B1 inhibition is a relevant mechanism for the interaction observed between CsA and atorvastatin.

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Section: Cyclosporine a But Not Tacrolimus Inhibits Oatp1b1mentioning

confidence: 74%

Cyclosporine A, but Not Tacrolimus, Shows Relevant Inhibition of Organic Anion-Transporting Protein 1B1-Mediated Transport of Atorvastatin

Amundsen¹,

Christensen²,

Zabihyan³

et al. 2010

Drug Metab Dispos

126

107

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“…Incomplete inhibition complicates the interpretation of reaction phenotyping studies since it cannot be determined if the remaining activity is a result of another metabolic route or simply incomplete inhibition. This exact scenario confounds the accurate determination of fraction of drug metabolized by a particular pathway and thus introduces error into key in vitro-in vivo predictions such as drug-drug interactions and is especially poignant for investigational drugs with intermediate I/K i ratios between 10 and 1 for which the uncertainty regarding the manifestation of a drug-drug interaction in vivo is increased (Bachmann and Lewis, 2005).…”

Section: Discussionmentioning

confidence: 99%

The Combination of Chemical and Antibody Inhibitors for Superior P450 3A Inhibition in Reaction Phenotyping Studies

Rock¹,

Foti²,

Pearson³

2008

Drug Metab Dispos

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ABSTRACT:Cytochrome P450 (P450) reaction phenotyping is a key process toward accurately determining the contribution of different P450s to the metabolism of new chemical entities. The significance of P450s to drug disposition has led to the identification of selective chemical and antibody inhibitors for individual P450 enzymes. Despite these advances, the maximal inhibition attainable is limited by the use of inhibitor concentrations that maintain selectivity for the individual P450s. Thus, most commercially available inhibitors produce a maximal inhibition of ϳ80%. Herein, the combination of chemical plus antibody inhibitors is explored to find whether P450 3A could be selectively and completely (>99%) inhibited by using both inhibitors simultaneously.The majority of marketed drugs are metabolized by members of the cytochrome P450 (P450) superfamily of enzymes (Wienkers and Heath, 2005). Given the limited number of P450 enzymes that contribute to the clearance of commercial therapeutics, P450s represent the primary source of clinically observed drug interactions in patients. In vitro techniques have evolved to enable the early estimation of drug interaction potential with preclinical drug candidates either as perpetrator or victim prior to clinical evaluation (Lu et al., 2003).The improved extrapolation of in vitro data to humans over the last decade is partially attributed to the inclusion of additional parameters that impact the scaling of in vitro data. For example, considering unbound fraction of drug during in vitro microsomal incubations and attempts to approximate the most appropriate inhibitor concentration in vivo can improve in vitro extrapolations (Margolis and Obach, 2003;Obach et al., 2005Obach et al., , 2006. Furthermore, a retrospective analysis of disparate in vitro estimates of drug interactions compared with clinically observed interactions illustrates that predictions can be improved when the fraction of drug metabolized through individual P450 pathways is accurately determined (Fig. 1) (Ito et al., 2005). P450 reaction phenotyping is used to determine fraction of drug metabolized by P450s and is possible in part because of the accumulation of compounds identified as selective inhibitors of individual P450 enzymes (Cai et al., 2004;Stresser et al., 2004;Walsky et al., 2005b). Additionally, the introduction of selective antibody inhibitors has expanded the diversity of inhibitors available to determine the involvement of different P450 pathways to a drug's clearance. However, commercial antibodies and chemical inhibitors typically do not yield complete inhibition of the P450 enzymes, especially at concentrations that maintain selectivity for the individual P450 enzymes. In the balance to achieve maximal yet selective inhibition of individual P450 enzymes the effective inhibitor concentrations typically result in inhibition up to 80%. The remaining 20% activity reduces the predictive nature of in vitro extrapolation techniques and increases the uncertainty regarding the potential activity from...

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“…The interactions due to drug metabolism can be, as mentioned above, based on phase 1 metabolism (mainly involving cytochrome P 450 isoenzymes) or, rather rare, on phase 2 metabolism involving, for example, Pglycoproteins (P-gp), which is relevant for outward bound transport processes, for example, in the intestinal wall, or on conjugation, for example, with glucuronic acid [43]. In case that a specific herb-drug interaction is identified, its clinical significance depends on the degree of accumulation and the therapeutic window of the respective drug [44]. Also the dosage, time of administration, galenic properties, and coadministration as well as intrinsic and extrinsic factors may be of importance.…”

Section: Pharmacokinetic Interactionsmentioning

confidence: 99%

Valerian: No evidence for Clinically Relevant interactions

Kelber¹,

Nieber²,

Kraft³

2012

Planta Med

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In recent popular publications as well as in widely used information websites directed to cancer patients, valerian is claimed to have a potential of adverse interactions with anticancer drugs. This questions its use as a safe replacement for, for example, benzodiazepines. A review on the interaction potential of preparations from valerian root (Valeriana officinalis L. root) was therefore conducted. A data base search and search in a clinical drug interaction data base were conducted. Thereafter, a systematic assessment of publications was performed. Seven in vitro studies on six CYP 450 isoenzymes, on p-glycoprotein, and on two UGT isoenzymes were identified. However, the methodological assessment of these studies did not support their suitability for the prediction of clinically relevant interactions. In addition, clinical studies on various valerian preparations did not reveal any relevant interaction potential concerning CYP 1A2, 2D6, 2E1, and 3A4. Available animal and human pharmacodynamic studies did not verify any interaction potential. The interaction potential of valerian preparations therefore seems to be low and thereby without clinical relevance. We conclude that there is no specific evidence questioning their safety, also in cancer patients.

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Predicting Inhibitory Drug—Drug Interactions and Evaluating Drug Interaction Reports Using Inhibition Constants

Abstract: We suggest that the use of Ki values of drugs purported to behave as CYP inhibitors be incorporated in the assessment of case reports that ascribe DDIs to inhibition of metabolism of one drug by another.

Cited by 91 publications

References 23 publications

Cyclosporine A, but Not Tacrolimus, Shows Relevant Inhibition of Organic Anion-Transporting Protein 1B1-Mediated Transport of Atorvastatin

Cyclosporine A, but Not Tacrolimus, Shows Relevant Inhibition of Organic Anion-Transporting Protein 1B1-Mediated Transport of Atorvastatin

The Combination of Chemical and Antibody Inhibitors for Superior P450 3A Inhibition in Reaction Phenotyping Studies

Valerian: No evidence for Clinically Relevant interactions

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