2002
DOI: 10.1208/ps040425
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Which concentration of the inhibitor should be used to predict in vivo drug interactions from in vitro data?

Abstract: When the metabolism of a drug is competitively or noncompetitively inhibited by another drug, the degree of in vivo interaction can be evaluated from the [I] u /K i ratio, where [I] u is the unbound concentration around the enzyme and K i is the inhibition constant of the inhibitor. In the present study, we evaluated the metabolic inhibition potential of drugs known to be inhibitors or substrates of cytochrome P450 by estimating their [I] u /K i ratio using literature data.The maximum concentration of the inh… Show more

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Cited by 77 publications
(61 citation statements)
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“…Using this equation, Ito et al succeeded in the accurate prediction of CYP-mediated DDI risks while minimizing the false-negative predictions and maximizing the true-positive predictions by the use of I u,in,max value compared with the use of unbound concentration of inhibitor in blood (I u,max ) and total concentration of inhibitor in blood (I max ). 32) Following this concept, we previously tried to predict the OATP1B1-and OATP1B3-mediated DDI potentials of several OATP inhibitor drugs in in vitro inhibition assays with gene expression systems. 11,33) As a result, by searching for drugs with estimated R values at a therapeutic dose of more than 2 among the drugs tested, clinically-relevant doses of cyclosporine A and rifampicin can inhibit both OATP1B1 and OATP1B3, while clarithromycin, rifamycin SV and indinavir can inhibit OATP1B1 at their clinical doses.…”
Section: Clinical Importance Of Oatp-mediated Drug-drug Interactionsmentioning
confidence: 99%
“…Using this equation, Ito et al succeeded in the accurate prediction of CYP-mediated DDI risks while minimizing the false-negative predictions and maximizing the true-positive predictions by the use of I u,in,max value compared with the use of unbound concentration of inhibitor in blood (I u,max ) and total concentration of inhibitor in blood (I max ). 32) Following this concept, we previously tried to predict the OATP1B1-and OATP1B3-mediated DDI potentials of several OATP inhibitor drugs in in vitro inhibition assays with gene expression systems. 11,33) As a result, by searching for drugs with estimated R values at a therapeutic dose of more than 2 among the drugs tested, clinically-relevant doses of cyclosporine A and rifampicin can inhibit both OATP1B1 and OATP1B3, while clarithromycin, rifamycin SV and indinavir can inhibit OATP1B1 at their clinical doses.…”
Section: Clinical Importance Of Oatp-mediated Drug-drug Interactionsmentioning
confidence: 99%
“…The "unbound drug hypothesis" is a widely accepted fundamental principle of pharmacokinetics, and there is increasing support for the use of unbound maximum inhibitor concentration entering the liver after p.o. administration ([I in,u ]) as the most appropriate surrogate for inhibitor concentration at the enzyme active site (Ito et al, 2002;McGinnity et al, 2005;Obach et al, 2006). Use of [I] total rather than [I] u has been proposed, usually for pragmatic reasons, to retrospectively account for observed interactions Brown et al, 2006) or as a cautious strategy in early drug discovery to avoid underestimation of in vivo interactions (Ito et al, 2002;McGinnity et al, 2005).…”
mentioning
confidence: 99%
“…administration ([I in,u ]) as the most appropriate surrogate for inhibitor concentration at the enzyme active site (Ito et al, 2002;McGinnity et al, 2005;Obach et al, 2006). Use of [I] total rather than [I] u has been proposed, usually for pragmatic reasons, to retrospectively account for observed interactions Brown et al, 2006) or as a cautious strategy in early drug discovery to avoid underestimation of in vivo interactions (Ito et al, 2002;McGinnity et al, 2005). The impact of nonspecific binding on estimating unbound K i is increasingly understood , and the sensitivity of IVIVE predictions to both the absorption rate constant of the inhibitor (k a ) and fraction metabolized by the inhibited pathway (f m ) of the substrate has been exemplified (Brown et al, 2005;McGinnity et al, 2005).…”
mentioning
confidence: 99%
“…5) [I] in,max,u ϭ f u ([I] max sys ϩk a Dose F a /Q h ) where f u represents the unbound fraction (0.002 6) ); [I] in,max,sys represents the concentration in the central compartment (642.3 ng/ml 7) ); k a represents first-order absorption rate constant (0.1 min…”
Section: Fig 2 Metabolism Of Pranlukast By Human B-lymphoblastoid Cmentioning
confidence: 99%
“…, assumed); Dose represents the clinical dose (225 mg); F a represents the fraction absorbed from the gastrointestinal tract (0.2, in-house data); Q h represents hepatic blood flow rate (1610 ml/min 5) ).…”
mentioning
confidence: 99%