The Pharmacokinetics of Low-Dose Thalidomide in Japanese Patients with Refractory Multiple Myeloma

Kamikawa, Rintaro; Ikawa, Kazuro; Morikawa, Norifumi; Asaoku, Hideki; Iwato, Koji; Sasaki, Ayako

doi:10.1248/bpb.29.2331

Cited by 10 publications

(5 citation statements)

References 15 publications

(14 reference statements)

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“…In Japan, thalidomide was similarly designated for the treatment of refractory multiple myeloma in 2005 as an "orphan" drug (Sembongi et al, 2008), and a decision regarding final approval is expected in 2008. Many clinical trials with thalidomide are ongoing for both anti-inflammatory and antiangiogenic activities (Vogelsang et al, 1992;Macpherson et al, 2003;Kamikawa et al, 2006;Breitkreutz and Anderson, 2008). Drug interactions between thalidomide and hormonal contraceptives have only been negative (Trapnell et al, 1998;Teo et al, 2000), and thalidomide has been considered to undergo very little metabolism by the P450 system, at least P450 3A4.…”

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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

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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.

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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

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“…However, it was withdrawn from most countries because of its high risk for teratogenicity. Recently, clinical investigations of thalidomide have been conducted in patients with diverse diseases, including multiple myeloma, rheumatoid arthritis, and human immunodeficiency virus infection [ 19 , 20 ] as the beneficial effects of thalidomide including anti-angiogenic, anti-viral, anti-inflammatory, and immunomodulatory activities were revealed [ 21 ]. Thalidomide shows anti-inflammatory activities, such as blocking TNF-α production by stimulated human peripheral blood mononuclear cells (PBMCs) [ 22 ] and by alveolar macrophages [ 23 , 24 ] and inhibiting IL-12 release [ 25 ].…”

Section: Resultsmentioning

confidence: 99%

Thalidomide Inhibits Alternative Activation of Macrophages In Vivo and In Vitro: A Potential Mechanism of Anti-Asthmatic Effect of Thalidomide

et al. 2015

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BackgroundThalidomide is known to have anti-inflammatory and immunomodulatory actions. However, the effect and the anti-asthmatic mechanism of thalidomide in the pathogenesis of asthmatic airways are not fully understood.ObjectiveThis study is designed to determine the effect and the potential mechanism of thalidomide in the pathogenesis of asthmatic airways using animal model of allergic asthma.MethodsSix-week-old female BALB/C mice were sensitized with alum plus ovalbumin (OVA) and were exposed to OVA via intranasal route for 3 days for challenge. Thalidomide 200 mg/kg was given via gavage twice a day from a day before the challenge and airway hyperresponsivenss (AHR), airway inflammatory cells, and cytokines in bronchoalveolar lavage fluids (BALF) were evaluated. The expression levels of pro-inflammatory cytokines and other mediators were evaluated using ELISA, real time (RT)-qPCR, and flow cytometry. CRL-2456, alveolar macrophage cell line, was used to test the direct effect of thalidomide on the activation of macrophages in vitro.ResultsThe mice with thalidomide treatment showed significantly reduced levels of allergen-induced BALF and lung inflammation, AHR, and the expression of a number of pro-inflammatory cytokines and mediators including Th2 related, IL-17 cytokines, and altered levels of allergen-specific IgG1/IgG2a. Of interesting note, thalidomide treatment significantly reduced expression levels of allergen- or Th2 cytokine-stimulated alternative activation of macrophages in vivo and in vitro.ConclusionThese studies highlight a potential use of thalidomide in the treatment of allergic diseases including asthma. This study further identified a novel inhibitory effect of thalidomide on alternative activation of macrophages as a potential mechanism of anti-asthmatic effect of thalidomide.

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“…Thalidomide has since been revealed to have a wide range of pharmacological effects, particularly anti-inflammatory and immunomodulatory activities (1,2). Therefore, it has been evaluated for the management of numerous inflammatory and autoimmune diseases, including multiple myeloma (3–5), rheumatoid arthritis (6,7), ankylosing spondylitis (8–10), Crohn’s disease (11,12), lupus erythematosus (13) and Behçet’s disease (14). Based on its confirmed efficacy, thalidomide was approved by the Food and Drug Administration (FDA) for the treatment of erythema nodosum leprosum in 1998 and multiple myeloma in 2006.…”

Section: Introductionmentioning

confidence: 99%

Determination of thalidomide concentration in human plasma by liquid chromatography-tandem mass spectrometry

Bai

Cui

Wang

et al. 2012

Experimental and Therapeutic Medicine

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A rapid, sensitive and specific analytical method based on high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) has been developed for the determination of thalidomide concentration in human plasma. The analyte and internal standard were extracted by liquid-liquid extraction with ether-dichloromethane (3:2, v/v) and separated on a TC-C18 column using methanol-10 mM ammonium acetate-formic acid (60:40:0.04, v/v/v) as the mobile phase at a flow rate of 0.9 ml/min. The detection was performed using an API 4000 triple quadrupole mass spectrometer in the positive electrospray ionization (ESI) mode and completed within 3.0 min. The multiple reaction monitoring (MRM) transitions were m/z 259.1→84.0 for the analyte and m/z 195.9→138.9 for temozolomide. The calibration curve exhibited a linear dynamic range of 2–1500 ng/ml (r>0.9991). The intra-and inter-day precisions (as relative standard deviation; RSD) were 6.8–13.5% and 4.3–5.0% respectively and the accuracy (as relative error; RE) was 2.0–3.5%. The recoveries and matrix effects were satisfactory in all the biological matrices examined. This method was successfully used in a pharmacokinetic study of thalidomide in healthy male volunteers receiving an oral administration of a 200-mg dose.

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The Pharmacokinetics of Low-Dose Thalidomide in Japanese Patients with Refractory Multiple Myeloma

Cited by 10 publications

References 15 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

Thalidomide Inhibits Alternative Activation of Macrophages In Vivo and In Vitro: A Potential Mechanism of Anti-Asthmatic Effect of Thalidomide

Determination of thalidomide concentration in human plasma by liquid chromatography-tandem mass spectrometry

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