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The effect of circadian rhythm on pharmacokinetics and metabolism of the Cdk inhibitor, roscovitine, in tumor mice model
Experimental Cancer Medicine, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
Experimental Cancer Medicine, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden, ; Department of Basic Medical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates, ; Department of Medical Biochemistry, Faculty of Medicine, Suez Canal University, Ismaileya, Egypt.ORCID iD: 0000-0001-5394-9082
INSERM, U 776 «Rythmes biologiques et cancers», Hôp. P. Brousse, Villejuif, France; University Paris-Sud, Orsay, France.
Department of Discovery Research, Medivir AB, Huddinge, Stockholm, Sweden.
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2015 (English)In: Chronobiology International, ISSN 0742-0528, E-ISSN 1525-6073, Vol. 32, no 5, p. 608-614Article in journal (Refereed) Published
Abstract [en]

Roscovitine is a selective Cdk-inhibitor that is under investigation in phase II clinical trials under several conditions, including chemotherapy. Tumor growth inhibition has been previously shown to be affected by the dosing time of roscovitine in a Glasgow osteosarcoma xenograft mouse model. In the current study, we examined the effect of dose timing on the pharmacokinetics, biodistribution and metabolism of this drug in different organs in B6D2F1 mice. The drug was orally administered at resting (ZT3) or activity time of the mice (ZT19) at a dose of 300 mg/kg. Plasma and organs were removed at serial time points (10, 20 and 30 min; 1, 2, 4, 6, 8, 12 and 24 h) after the administration. Roscovitine and its carboxylic metabolite concentrations were analyzed using HPLC-UV, and pharmacokinetic parameters were calculated in different organs. We found that systemic exposure to roscovitine was 38% higher when dosing at ZT3, and elimination half-life was double compared to when dosing at ZT19. Higher organ concentrations expressed as (organ/plasma) ratio were observed when dosing at ZT3 in the kidney (180%), adipose tissue (188%), testis (132%) and lungs (112%), while the liver exposure to roscovitine was 120% higher after dosing at ZT19. The metabolic ratio was approximately 23% higher at ZT19, while the intrinsic clearance (CLint) was approximately 67% higher at ZT19, indicating faster and more efficient metabolism. These differences may be caused by circadian differences in the absorption, distribution, metabolism and excretion processes governing roscovitine disposition in the mice. In this article, we describe for the first time the chronobiodistribution of roscovitine in the mouse and the contribution of the dosing time to the variability of its metabolism. Our results may help in designing better dosing schedules of roscovitine in clinical trials.

Place, publisher, year, edition, pages
Abingdon, Oxfordshire, United Kingdom: Taylor & Francis, 2015. Vol. 32, no 5, p. 608-614
Keywords [en]
Biodistribution; chronopharmacology; metabolism; pharmacokinetics; roscovitine
National Category
Pediatrics
Identifiers
URN: urn:nbn:se:liu:diva-184585DOI: 10.3109/07420528.2015.1022782ISI: 000358065800004PubMedID: 25938685Scopus ID: 2-s2.0-84931825306OAI: oai:DiVA.org:liu-184585DiVA, id: diva2:1654119
Note

Funding: This research was funded by generous grants from the Swedish Cancer Society (Cancerfonden), the Swedish Childhood Cancer Foundation (Barncancerfonden) and Karolinska Institutet Foundation (KI Fonder).

Available from: 2022-04-26 Created: 2022-04-26 Last updated: 2022-05-02Bibliographically approved

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El-Serafi, Ahmed Taher

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