Prediction of the Metabolic Interaction of Nateglinide with Other Drugs Based on in Vitro Studies

Takanohashi, Toshiyuki; Koizumi, Tomonori; Mihara, Ryuichi; Okudaira, Kazuho

doi:10.2133/dmpk.22.409

Cited by 20 publications

(15 citation statements)

References 27 publications

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“…Throughout the present study, a wide range of (S)-(ϩ)-IBU and (R)-(Ϫ)-IBU concentrations was used (1-500 M). Such a range encompasses the clinically relevant free (ϳ1 M) and total (ϳ100 M) plasma concentrations of each enantiomer (Davies, 1998;Andersson et al, 2004;Takanohashi et al, 2007). Integration of the above in vitro data, with known human ADME information, may help rationalize reports describing IBU PK-P450 inhibitor combinations and IBU PK-P450 genotype associations (Kirchheiner et al, 2002;Garcia-Martin et al, 2004;Martinez et al, 2005;Hynninen et al, 2006;Bell et al, 2007;Tornio et al, 2007).…”

Section: Cyp2c8 Plays a Minor Role In (R)-(؊)-ibu (<10%) And (S)-(؉)-mentioning

confidence: 99%

Confirmation That Cytochrome P450 2C8 (CYP2C8) Plays a Minor Role in (S)-(+)- and (R)-(-)-Ibuprofen Hydroxylation in Vitro

Chang¹,

Li²,

Traeger³

et al. 2008

Drug Metab Dispos

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ABSTRACT:Various groups have sought to determine the impact of CYP2C8 genotype (and CYP2C8 inhibition) on the pharmacokinetics (PK) of ibuprofen (IBU) enantiomers. However, the contribution of cytochrome P450 2C8 (CYP2C8) in human liver microsomes (HLMs) has not been reported. Therefore, in vitro cytochrome P450 (P450) reaction phenotyping was conducted with selective inhibitors of cytochrome P450 2C9 (CYP2C9) and CYP2C8. In the presence of HLMs, sulfaphenazole (CYP2C9 inhibitor), and anti-CYP2C9 monoclonal antibodies (mAbs) inhibited (73-100%) the 2-and 3-hydroxylation of both IBU enantiomers (1 and 20 M). At a higher IBU concentration (500 M), the same inhibitors were less able to inhibit the 2-hydroxylation of There has been continued interest in the safety and ADME properties of cyclooxygenase inhibitors. This interest has extended to 2-(4-isobutylphenyl)propionic acid (ibuprofen, IBU), which is administered as a racemic mixture of (S)-(ϩ)-and (R)-(Ϫ)-enantiomers (Rodrigues, 2005;Agúndez et al., 2007;Pilotto et al., 2007;Blanco et al., 2008). The metabolism of both enantiomers is complex and involves direct (acyl) glucuronidation, 2-hydroxylation, and 3-hydroxylation (methyl hydroxylation) (Fig. 1). Once formed, the 3-hydroxy metabolite is converted almost completely to the corresponding carboxy derivative via cytosolic dehydrogenases (Rudy et al., 1991;Hamman et al., 1997;Davies, 1998). Only (R)-(Ϫ)-IBU undergoes (unidirectional) chiral inversion, which is significant because pharmacological activity after a racemic dose is attributed largely to the (S)-(ϩ)-enantiomer (Davies, 1998;Hao et al., 2005;Ding et al., 2007). Overall, it seems that P450-dependent metabolism accounts for approximately 70 and 30% of (S)-(ϩ)-IBU and (R)-(Ϫ)-IBU clearance, respectively (Rodrigues, 2005). At first glance, the pharmacokinetic profile of the latter is expected to be minimally affected by P450 inhibitors and genotype (e.g., CYP2C9*1/*3, CYP2C9*3/*3; CYP2C8*1/*3, CYP2C8*3/*3). (S)-(؉)-IBU (32-52%) and (R)-(؊)-IBU (30-64%), whereas the 3-hydroxylation of (S)-(؉)-IBU and (R)-(؊)-Currently available in vitro data show that CYP2C9 plays a major role (Ͼ70%) in the oxidative metabolism of racemic IBU and its individual enantiomers. However, hydroxylation of both enantiomers has also been measured with rCYP2C8 and other P450s (CYP3A4 and CYP2C19) (Leeman et al., 1993;Hamman et al., 1997;McGinnity et al., 2000). Such data have led various groups to conclude that both CYP2C forms catalyze the oxidative metabolism of IBU, and attempts have been made to evaluate the impact of both CYP2C9 and CYP2C8 genotype on the PK, pharmacodynamics, and side-effect profile of IBU enantiomers (Kirchheiner et al., 2002;Garcia-Martin et al., 2004; Martinez et al., 2005;Pilotto et al., 2007;Blanco et al., 2008). Clinical drug interaction studies with known inhibitors of CYP2C9 (e.g., fluconazole) and CYP2C8 (e.g., gemfibrozil) have been conducted also (Hynninen et al., 2006;Tornio et al., 2007).However, it is worth noting that CYP2C8-selective chemica...

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Section: Cyp2c8 Plays a Minor Role In (R)-(؊)-ibu (<10%) And (S)-(؉)-mentioning

confidence: 99%

Confirmation That Cytochrome P450 2C8 (CYP2C8) Plays a Minor Role in (S)-(+)- and (R)-(-)-Ibuprofen Hydroxylation in Vitro

Chang¹,

Li²,

Traeger³

et al. 2008

Drug Metab Dispos

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“…It is worth noting that Dostalek et al reported that only patients with poor glycemic control exhibit changes in the activities of metabolic enzymes. Moreover, previous studies have demonstrated that the metabolism of tolbutamide by CYP2C9 is not changed in diabetes patients and that metformin is unlikely to exert any influence on carvedilol pharmacokinetics because apparently metformin is not a substrate, inducer, or inhibitor of CYP enzymes …”

Section: Discussionmentioning

confidence: 99%

Effects of Type 2 Diabetes Mellitus in Patients on Treatment With Glibenclamide and Metformin on Carvedilol Enantiomers Metabolism

Nardotto

Coelho

Paiva

et al. 2017

The Journal of Clinical Pharmacology

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Carvedilol is available in clinical practice as a racemate in which (S)-(-)-carvedilol is a β- and α -adrenergic antagonist and (R)-(+)-carvedilol is only an α -adrenergic antagonist. Carvedilol is mainly metabolized by glucuronidation, by CYP2D6 to hydroxyphenylcarvedilol (OHC), and by CYP2C9 to O-desmethylcarvedilol (DMC). This study evaluated the pharmacokinetics of carvedilol enantiomers and their metabolites OHC and DMC in healthy volunteers (n = 13) and in type 2 diabetes mellitus patients with good glycemic control (n = 13). The healthy subjects were enrolled to receive either a 25-mg oral single dose of carvedilol alone (no DDI) or carvedilol simultaneously with 5 mg glibenclamide and 500 mg metformin (DDI), whereas type 2 diabetes mellitus patients who were on long-term treatment with glibenclamide (5 mg/8 h) and metformin (500 mg/8 h) were enrolled to receive only a single oral dose of 25 mg carvedilol. The plasma concentrations of the (R)-(+)-carvedilol, (R)-(+)-DMC, and (R)-(+)-OHC were higher than those of (S)-(-)-carvedilol, (S)-(-)-DMC, and (S)-(-)-OHC in all investigated groups. The pharmacokinetics of the carvedilol enantiomers did not differ between the groups. However, the AUC values of the DMC enantiomers were lower in the type 2 diabetes mellitus patients than in the healthy volunteers (DDI and no DDI) [(R)-(+), 6.9, 10.4, 11.9 ng·h/mL; and (S)-(-), 2.4, 4.3, 4.0 ng·h/mL, respectively]. In contrast, the AUC values of the OHC enantiomers were higher in the type 2 diabetes mellitus patients [(R)-(+), 13.9, 6.6, 4.9 ng·h/mL; and (S)-(-), 7.2, 1.5, 1.5 ng·h/mL], which explains the fact that the carvedilol pharmacokinetics was unchanged.

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“…Unlike many non-aspirin NSAIDs, aspirin is not primarily metabolized by CYP2C9 37–40. Thus, it is unlikely that this association reflects genotype-specific differences in tolerance to aspirin therapy.…”

Section: Discussionmentioning

confidence: 99%

Cytochrome P450 2C9 Variants Influence Response to Celecoxib for Prevention of Colorectal Adenoma

et al. 2009

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Prediction of the Metabolic Interaction of Nateglinide with Other Drugs Based on in Vitro Studies

Cited by 20 publications

References 27 publications

Confirmation That Cytochrome P450 2C8 (CYP2C8) Plays a Minor Role in (S)-(+)- and (R)-(-)-Ibuprofen Hydroxylation in Vitro

Confirmation That Cytochrome P450 2C8 (CYP2C8) Plays a Minor Role in (S)-(+)- and (R)-(-)-Ibuprofen Hydroxylation in Vitro

Effects of Type 2 Diabetes Mellitus in Patients on Treatment With Glibenclamide and Metformin on Carvedilol Enantiomers Metabolism

Cytochrome P450 2C9 Variants Influence Response to Celecoxib for Prevention of Colorectal Adenoma

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