Small-Dosing Clinical Study: Pharmacokinetic, Pharmacogenomic (SLCO2B1 and ABCG2), and Interaction (Atorvastatin and Grapefruit Juice) Profiles of 5 Probes for OATP2B1 and BCRP

Kashihara, Yushi; Ieiri, Ichiro; Yoshikado, Takashi; Maeda, Kazuya; Fukae, Masato; Kimura, Miyuki; Hirota, Tomoyoshi; Matsuki, Shunji; Irie, Shin; Izumi, Noritomo; Kusuhara, Hiroyuki; Sugiyama, Yuichi

doi:10.1016/j.xphs.2017.03.010

Cited by 44 publications

(35 citation statements)

References 32 publications

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“…31 As part of the present study, we assessed the association of SLCO1B1 and ABCG2 genotypes with the dose-dependent inhibition of OATP1B by rifampicin. As expected from previous reports, 32,33 the volunteers carrying ABCG2 mutant alleles showed higher plasma concentrations of rosuvastatin ( Figure S6) with lower AUCR in the presence of rifampicin as compared with those with wild-type (ABCG2). Importantly, ABCG2 genotype was not shown to impact the concentrations of any of the endogenous compounds ( Figure S7).…”

Section: Articlesupporting

confidence: 90%

Dose‐Dependent Inhibition of OATP1B by Rifampicin in Healthy Volunteers: Comprehensive Evaluation of Candidate Biomarkers and OATP1B Probe Drugs

Mori

Kimoto

Rago

et al. 2020

Clin Pharma and Therapeutics

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137

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To address the most appropriate endogenous biomarker for drug–drug interaction risk assessment, eight healthy subjects received an organic anion transporting polypeptide 1B (OATP1B) inhibitor (rifampicin, 150, 300, and 600 mg), and a probe drug cocktail (atorvastatin, pitavastatin, rosuvastatin, and valsartan). In addition to coproporphyrin I, a widely studied OATP1B biomarker, we identified at least 4 out of 28 compounds (direct bilirubin, glycochenodeoxycholate‐3‐glucuronide, glycochenodeoxycholate‐3‐sulfate, and hexadecanedioate) that presented good sensitivity and dynamic range in terms of the rifampicin dose‐dependent change in area under the plasma concentration‐time curve ratio (AUCR). Their suitability as OATP1B biomarkers was also supported by the good correlation of AUC0‐24h between the endogenous compounds and the probe drugs, and by nonlinear regression analysis (AUCR−1 vs. rifampicin plasma Cmax (maximum total concentration in plasma)) to yield an estimate of the inhibition constant of rifampicin. These endogenous substrates can complement existing OATP1B‐mediated drug–drug interaction risk assessment approaches based on agency guidelines in early clinical trials.

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Section: Articlesupporting

confidence: 90%

Dose‐Dependent Inhibition of OATP1B by Rifampicin in Healthy Volunteers: Comprehensive Evaluation of Candidate Biomarkers and OATP1B Probe Drugs

Mori

Kimoto

Rago

et al. 2020

Clin Pharma and Therapeutics

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137

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“…though no significant changes in the plasma concentrations of these drugs were observed upon coadministration of atorvastatin, a strong inhibitor of OATP2B1 (Kashihara et al, 2017). This implies that osmolalitydependent water movement may account for the decrease in plasma concentration of various drugs by coadministration of not only AJ, but also GFJ and other beverages.…”

Section: Downloaded Frommentioning

confidence: 95%

Effect of Osmolality on the Pharmacokinetic Interaction between Apple Juice and Atenolol in Rats

et al. 2019

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A recent clinical study reported that the ingestion of apple juice (AJ) markedly reduced the plasma concentration of atenolol; however, our in vitro study showed that atenolol may not be a substrate of organic anion transporting polypeptide 2B1 (OATP2B1), so this AJ-atenolol interaction cannot be explained by inhibition of OATP2B1. On the other hand, we more recently showed that the solution osmolality influences gastrointestinal (GI) water volume, and this may indirectly affect intestinal drug absorption. In this study, we examined whether the osmolality dependence of water dynamics can account for AJ-atenolol interactions by evaluating the GI water volume and the atenolol aborption in the presence of AJ in rats. Water absorption was highest in purified water, followed by saline and isosmotic mannitol solution, and the lowest in AJ, confirming that water absorption is indeed osmolality-dependent. Interestingly, AJ showed apparent water secretion into the intestinal lumen. The intestinal concentration of FD-4, a nonpermeable compound, after administration in AJ was lower than the initial concentration, whereas that in purified water was greater than the initial concentration. Further, the fraction of atenolol absorbed in intestine was significantly lower in AJ or hyperosmotic mannitol solution (adjusted to the osmolality of AJ) than after administration in purified water. Comparable results were observed in an in vivo pharmacokinetic study in rats. Our results indicate that orally administered AJ has a capacity to modulate luminal water volume depending on the osmolality, and this effect may result in significant AJ-atenolol interactions.

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“…They are involved in certain classes of peptidomimetics such as angiotensin converting enzyme (ACE) inhibitors (captopril and enalapril), but even here different examples of the class are not substrates. [34] OATP2B1 has a broader substrate selectivity and, together with passive permeability, has been shown to contribute to the intestinal absorption of lipophilic acids, such as fexofenadine, [35] atorvastatin, [36] pitavastatin [37] and rosuvastatin. [38] Levodopa, the cornerstone in Parkinson therapy, is absorbed mainly through amino acid transporters located predominately in the small intestine.…”

Section: Impact Of Transporters On Oral Absorptionmentioning

confidence: 99%

The Critical Role of Passive Permeability in Designing Successful Drugs

Artursson

Avdeef³

et al. 2020

ChemMedChem

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Passive permeability is a key property in drug disposition and delivery. It is critical for gastrointestinal absorption, brain penetration, renal reabsorption, defining clearance mechanisms and drug-drug interactions. Passive diffusion rate is translatable across tissues and animal species, while the extent of absorption is dependent on drug properties, as well as in vivo physiology/pathophysiology. Design principles have been developed to guide medicinal chemistry to enhance absorption, which combine the balance of aqueous solubility, permeability and the sometimes unfavorable compound characteristic demanded by the target. Permeability assays have been implemented that enable rapid development of structurepermeability relationships for absorption improvement. Future advances in assay development to reduce nonspecific binding and improve mass balance will enable more accurately measurement of passive permeability. Design principles that integrate potency, selectivity, passive permeability and other ADMET properties facilitate rapid advancement of successful drug candidates to patients.

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Small-Dosing Clinical Study: Pharmacokinetic, Pharmacogenomic (SLCO2B1 and ABCG2), and Interaction (Atorvastatin and Grapefruit Juice) Profiles of 5 Probes for OATP2B1 and BCRP

Cited by 44 publications

References 32 publications

Dose‐Dependent Inhibition of OATP1B by Rifampicin in Healthy Volunteers: Comprehensive Evaluation of Candidate Biomarkers and OATP1B Probe Drugs

Dose‐Dependent Inhibition of OATP1B by Rifampicin in Healthy Volunteers: Comprehensive Evaluation of Candidate Biomarkers and OATP1B Probe Drugs

Effect of Osmolality on the Pharmacokinetic Interaction between Apple Juice and Atenolol in Rats

The Critical Role of Passive Permeability in Designing Successful Drugs

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