Pharmacokinetics of acitretin and etretinate

Wiegand, U.; Chou, Ruby C.

doi:10.1016/s0190-9622(98)70441-4

Cited by 64 publications

(47 citation statements)

References 22 publications

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“…Misoprostol and verapamil are both class 1 compounds based on their high membrane permeability and high solubility characteristics. Miconazole, acitretin, cholecalciferol, repaglinide, and salmeterol can be classified as class 2 drugs based on the following observations: miconazole displays high permeability (rapidly absorbed) and low bioavailability (ϳ30%), undergoing extensive metabolism with less than 1% of the administered dose excreted in the urine unchanged (Stevens, 1983); oral bioavailability of acitretin, cholecalciferol, and repaglinide is 56 to 60%; oral absorption of acitretin increases when administered with food (Wiegand and Chou, 1998); cholecalciferol and salmeterol are extensively metabolized and readily absorbed; clinical studies indicate that known P-gp substrates such as phenobarbital (Wikinski, 2005) and phenytoin (Bialecka et al, 2005) reduce plasma levels of vitamin D, suggesting a possible P-gp-mediated DDI involving cholecalciferol; and a DDI was recently observed during the coadministration of repaglinide with the known P-gp inhibitor cyclosporine A, which markedly increases the plasma concentrations of repaglinide in humans (Kajosaari et al, 2005). Based on our current studies and these clinical observations, we can deduce that the affinity of repaglinide for P-gp significantly contributes to potential DDI with other P-gp substrates or inhibitors.…”

Section: Database Mining To Identify P-gp Substrates and Inhibitorsmentioning

confidence: 99%

Rapid Identification of P-glycoprotein Substrates and Inhibitors

Chang

Bahadduri²,

Polli³

et al. 2006

Drug Metab Dispos

135

105

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ABSTRACT:Identifying molecules that interact with P-glycoprotein (P-gp) is important for drug discovery but is also generally reliant on timeconsuming in vitro and in vivo studies. As an alternative approach, the current study applied pharmacophore models and database screening to rapidly retrieve molecules that bind as substrates or inhibitors for P-gp from commercial databases and then confirmed their affinity as inhibitors in vitro. Seven molecules (acitretin, cholecalciferol, misoprostol, nafcillin, repaglinide, salmeterol, and telmisartan) with no published details for P-gp affinity, one positive control inhibitor (miconazole), and two negative control molecules (phenelzine and zonisamide) were selected for testing. The MDCK-MDR1 in vitro cell model was used to confirm their inhibitory effect on [ 3 H]digoxin transport, and the ATPase assay was used as an additional in vitro tool to indicate P-gp activation. All seven test drugs were confirmed to have P-gp affinity. Additionally, our experimental results provided plausible explanations for the published pharmacokinetic profiles of the tested drugs and their classification according to the biopharmaceutics and drug disposition classification system. In this study, we showed the successful application of pharmacophore models to accurately predict P-gp binding, which holds promise to anticipate drug-drug interactions from screening drug databases and a priori prediction of novel P-gp inhibitors or substrates.Assessment of P-glycoprotein (P-gp, ABCB1) affinity in humans is a rate-limiting step in the identification of drug efficacy and safety. Apart from serving as a key factor in the natural detoxification mechanism in various human tissues, expression of P-gp also mediates efflux of xenobiotics. This generally results in reduced bioavailability as a result of increased hepatic, renal, and/or intestinal clearance of substrate drugs. Because of its frequent involvement in drug absorption, distribution, metabolism, and excretion, screening for in vivo and in vitro P-gp-mediated transport has become an essential component of the drug discovery process; this, in turn, may have led to the mounting costs of identifying clinical drug candidates. Attempts to coadminister P-gp modulators, inhibitors, or inducers to increase cellular availability by blocking the actions of P-gp have been met with limited success. As a result, there is a great need to identify whether a new chemical entity has affinity for P-gp and to understand the effects of P-gp on drug pharmacokinetics and pharmacodynamics. Thus, the rapid identification of P-gp substrates or inhibitors would be advantageous.Despite its overall significance, P-gp is poorly characterized at the atomic level, in large part because of the intrinsic difficulties involved in membrane protein crystallization. As an alternative, computational modeling of transporters has aided our understanding and has significantly increased our knowledge of transporter mechanisms and drug-transporter interactions. However, in the case of ...

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Section: Database Mining To Identify P-gp Substrates and Inhibitorsmentioning

confidence: 99%

Rapid Identification of P-glycoprotein Substrates and Inhibitors

Chang

Bahadduri²,

Polli³

et al. 2006

Drug Metab Dispos

135

105

View full text Add to dashboard Cite

show abstract

“…2 Despite of the extensive and successful clinical usage of this class of compounds in the treatment of skin diseases, the actual mechanism of their pharmacological action has not yet been clearly identified.…”

Section: Introductionmentioning

confidence: 99%

Single Crystal and Powder Diffraction Characterization of Three Polymorphic Forms of Acitretin

Malpezzi

Magnone²,

Masciocchi

et al. 2005

Journal of Pharmaceutical Sciences

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“…Synthetic retinoid are stored in the liver as that of Vitamin A 1 . Isotretinoin and acitretin are comparatively water soluble whereas etretinate is 50 times more lipophilic than acitretin which makes the use of acitretin more advantageous in treating psoriasis especially in women with child bearing potential 6 . Retinoids are metabolized in liver by the induction of oxidative metabolism [7][8] .…”

Section: Fig 1: Mechanism Of Actionmentioning

confidence: 99%

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IJPSR

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Pharmacokinetics of acitretin and etretinate

Cited by 64 publications

References 22 publications

Rapid Identification of P-glycoprotein Substrates and Inhibitors

Rapid Identification of P-glycoprotein Substrates and Inhibitors

Single Crystal and Powder Diffraction Characterization of Three Polymorphic Forms of Acitretin

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