In vitro metabolism of cyclosporine A by human kidney CYP3A5

Dai, Yang; Iwanaga, Kazunori; Lin, Yvonne S.; Hébert, Mary F.; Davis, Connie L.; Huang, Weili; Kharasch, Evan D.; Thummel, Kenneth E.

doi:10.1016/j.bcp.2004.07.012

Cited by 117 publications

(92 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Midazolam 1Ј-and 4-hydroxylation activities were determined using high-performance liquid chromatography (Emoto et al, 2008). Cyclosporine A oxidation was determined by the disappearance of parent compound (Dai et al, 2004). In brief, a typical incubation mixture (total volume of 0.25 ml) contained microsomal protein (0.25 mg/ml) or recombinant P450 (0.06 M), an NADPH-generating system (0.25 mM NADP ϩ , 2.5 mM glucose 6-phosphate, and 0.25 unit/ml glucose 6-phosphate dehydrogenase), and substrate and/or thalidomide in 0.10 M potassium phosphate buffer (pH 7.4), unless otherwise specified.…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Drug Interactions of Thalidomide with Midazolam and Cyclosporine A: Heterotropic Cooperativity of Human Cytochrome P450 3A5

Okada

Murayama²,

Yanagida³

et al. 2008

Drug Metab Dispos

View full text Add to dashboard Cite

ABSTRACT:There is growing clinical interest of thalidomide because of its immunomodulatory and antiangiogenic properties, despite its teratogenicity. However, little information about thalidomide has been reported regarding its precise effects on drug-metabolizing enzymes. We investigated the effects of thalidomide on cytochrome P450 (P450) enzymes in human liver microsomes to clarify the potential for possible drug interactions. Thalidomide inhibited S-mephenytoin 4-hydroxylation activities of recombinant P450 2C19 and human liver microsomes: the apparent concentration of thalidomide producing 50% inhibition was approximately 270 M for P450 2C19. Midazolam 4-hydroxylation activities were suppressed by thalidomide, but activities of 1-hydroxylation and total midazolam oxidation and testosterone 6␤-hydroxylation were enhanced in the presence of thalidomide. Recombinant P450 3A5 was found to have altered kinetics at clinically relevant concentrations of thalidomide (10-30 M). P450 3A4 was also affected, but only at higher thalidomide concentrations. Enhanced midazolam hydroxylation by thalidomide was also seen in liver microsomal samples harboring the CYP3A5*1 allele. Similarly enhanced rates of cyclosporine A clearance were observed in P450 3A5 and liver microsomes expressing P450 3A5 in the presence of thalidomide. A proposed effector constant for thalidomide corresponded roughly to its clinical plasma levels. Docking studies with a P450 3A5 homology model, based on the published structure of P450 3A4, revealed close interaction between thalidomide and the heme of P450 3A5. The present results suggest that total midazolam metabolism or cyclosporine A clearance may be increased by thalidomide in a dose-dependent manner. Unexpected drug interactions involving thalidomide might occur via heterotropic cooperativity of polymorphic P450 3A5.

show abstract

Section: Methodsmentioning

confidence: 99%

“…On the other hand, midazolam 1Ј-hydroxylation activity (v) shows a substrate-inhibition manner with the eq. 3 formula, including the substrate inhibition constant K s (Dai et al, 2004):…”

Section: Methodsmentioning

confidence: 99%

Drug Interactions of Thalidomide with Midazolam and Cyclosporine A: Heterotropic Cooperativity of Human Cytochrome P450 3A5

Okada

Murayama²,

Yanagida³

et al. 2008

Drug Metab Dispos

View full text Add to dashboard Cite

show abstract

“…When a drug is administered, it is first absorbed in the intestine, and different proteins in the intestinal wall can determine the amount that finally passes into the blood. The calcineurin inhibitors (CNIs), the mammalian target of rapamycin (mTOR) inhibitors and corticosteroids are all metabolized by the oxidative enzymes in the cytochrome (CYP) 3A family (Dai et al, 2004(Dai et al, , 2006Kamdem et al, 2005) and are substrates for the P-glycoprotein (P-gp) (Miller et al, 1997;Saeki et al, 1993). They work together to form an active barrier to drug absorption, limiting the oral bioavailability of the CNIs and mTOR inhibitors (Zhang & Benet, 2001).…”

Section: Pharmacokinetics and Pharmacogeneticsmentioning

confidence: 99%

Pharmacogenetics and Renal Transplantation

Cheung¹

2011

Kidney Transplantation - New Perspectives

View full text Add to dashboard Cite

“…[8][9][10][11][12] However, in these reactions, a minor contribution of CYP3A5 may be demonstrated in the future when detection methods for the metabolite have been improved. In contrast, reactions which are predominantly catalyzed by CYP3A5 have not been reported.…”

Section: Metabolic Activity Of Cyp3a4 and Cyp3a5mentioning

confidence: 99%

Comparison of the Contributions of Cytochromes P450 3A4 and 3A5 in Drug Oxidation Rates and Substrate Inhibition

Niwa

Murayama

Yamazaki

2010

JOURNAL OF HEALTH SCIENCE

View full text Add to dashboard Cite

A meta-analysis was performed on the reported literature regarding followings. First, values of the MichaelisMenten constants (K m ), maximal velocities (V max ), and intrinsic clearance (V max /K m ) and the metabolic activities mediated by human cytochrome P450 3A4 and/or 3A5; second, inhibition constants (K i ); and third, maximum inactivation rate constants (k inact ) to establish the contribution of P450 3A5 to drug metabolism. At least 120 of the 127 metabolic reactions investigated (> 94%) were catalyzed by P450 3A4 and by P450 3A5. In the 73 metabolic reactions for which data were available, the mean P450 3A5/P450 3A4 ratios of K m , V max , and V max /K m values were 1.93, 1.25, and 1.20, respectively, but the median ratios were 1.17, 0.64, and 0.56, respectively. In 14-18% of the metabolic reactions, the V max and V max /K m values for P450 3A5 were more than twice those for P450 3A4. The K i values for P450 3A5 were on average approximately 5 times those for P450 3A4. Five of 13 mechanism-based inhibitors of P450 3A4 (38%) did not exhibit similar mechanism-based inhibition of P450 3A5. These collective findings give insight into the contribution of polymorphic P450 3A5 to drug metabolism and adverse drug interactions.

show abstract

In vitro metabolism of cyclosporine A by human kidney CYP3A5

Cited by 117 publications

References 42 publications

Drug Interactions of Thalidomide with Midazolam and Cyclosporine A: Heterotropic Cooperativity of Human Cytochrome P450 3A5

Drug Interactions of Thalidomide with Midazolam and Cyclosporine A: Heterotropic Cooperativity of Human Cytochrome P450 3A5

Pharmacogenetics and Renal Transplantation

Comparison of the Contributions of Cytochromes P450 3A4 and 3A5 in Drug Oxidation Rates and Substrate Inhibition

Contact Info

Product

Resources

About