Stability, pKa and plasma protein binding of roscovitine

Vita, Marina; Abdel‐Rehim, Mohamed; Nilsson, Christína; Hassan, Zuzana; Skansen, Patrik; Wan, Hong; Meurling, Lennart; Hassan, Moustapha

doi:10.1016/j.jchromb.2005.04.014

Cited by 49 publications

(23 citation statements)

References 36 publications

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“…However, the specific effect of temperature on the rifampin-protein complex was not mentioned there or in the literature. For other drugs, an increase in experimental ultrafiltration temperatures has been associated with an increase in the free fraction (39)(40)(41), but as far as we know this has not been reported for rifampin. Indeed, we found that measurement of free rifampin at 37°C resulted in a small increase in the rifampin-free fraction (mean change in free fraction, ϩ1.2%; median change, ϩ1.1%; range, Ϫ0.7 to ϩ3.5%, n ϭ 10 rifampin concentrations measured, P ϭ 0.029 [paired t test]) (unpublished data).…”

Section: Discussionmentioning

confidence: 76%

Exposure to Total and Protein-Unbound Rifampin Is Not Affected by Malnutrition in Indonesian Tuberculosis Patients

Brake

Ruslami

Later-Nijland

et al. 2015

Antimicrob Agents Chemother

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Overall, a marked 2-fold interindividual variation in the free fraction was observed (7.6 to 15.0%; n ‫؍‬ 36). Nutritional status and BMI do not appear to have a major effect on total and protein-unbound pharmacokinetic parameters of rifampin in Indonesian subjects. The large interindividual variability in the free fraction of rifampin suggests that protein-unbound rather than total rifampin concentrations should preferably be used to study exposure-response relationships.

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Section: Discussionmentioning

confidence: 76%

Exposure to Total and Protein-Unbound Rifampin Is Not Affected by Malnutrition in Indonesian Tuberculosis Patients

Brake

Ruslami

Later-Nijland

et al. 2015

Antimicrob Agents Chemother

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“…The human plasma protein binding of BI 201335 was determined by equilibrium dialysis using rotating chambers as previously described (38). The plasma chamber containing BI 201335 (1 mg/ml) was separated by a cellulose dialysis membrane (molecular size cutoff, 12 to 14 kDa) from the chamber containing only 100 mM phosphate (pH 7.4) buffer.…”

Section: Methodsmentioning

confidence: 99%

“…The chambers were incubated for 6 h at 37°C with a rotation rate of 25 rpm. Plasma protein binding (as a percentage) was calculated as previously described (38).…”

Section: Methodsmentioning

confidence: 99%

Preclinical Characterization of BI 201335, a C-Terminal Carboxylic Acid Inhibitor of the Hepatitis C Virus NS3-NS4A Protease

White

Llinàs‐Brunet

Amad

et al. 2010

Antimicrob Agents Chemother

106

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BI 201335 is a hepatitis C virus (HCV) NS3-NS4A (NS3 coexpressed with NS4A) protease inhibitor that has been shown to have potent clinical antiviral activity. It is a highly optimized noncovalent competitive inhibitor of full-length NS3-NS4A proteases of HCV genotypes 1a and 1b with K i values of 2.6 and 2.0 nM, respectively. K i values of 2 to 230 nM were measured against the NS3-NS4A proteases of HCV genotypes 2 to 6, whereas it was a very weak inhibitor of cathepsin B and showed no measurable inhibition of human leukocyte elastase. BI 201335 was also shown to be a potent inhibitor of HCV RNA replication in vitro with 50% effective concentrations (EC 50 s) of 6.5 and 3.1 nM obtained in genotype 1a and 1b replicon assays. Combinations of BI 201335 with either interferon or ribavirin had additive effects in replicon assays. BI 201335 had good permeability in Caco-2 cell assays and high metabolic stability after incubation with human, rat, monkey, and dog liver microsomes. Its good absorption, distribution, metabolism, and excretion (ADME) profile in vitro, as well as in rat, monkey, and dog, predicted good pharmacokinetics (PK) in humans. Furthermore, drug levels were significantly higher in rat liver than in plasma, suggesting that distribution to the target organ may be especially favorable. BI 201335 is a highly potent and selective NS3-NS4A protease inhibitor with good in vitro and animal ADME properties, consistent with its good human PK profile, and shows great promise as a treatment for HCV infection. Chronic hepatitis C virus (HCV) infection affects 130 to 170 million individuals worldwide (14). The etiologic agent is a small enveloped single-stranded RNA virus belonging to the Flaviviridae family, Hepacivirus genus (32). Although present in human populations for thousands of years, it was discovered only 20 years ago as the causative agent of non-A, non-B hepatitis (6). The HCV genome consists of approximately 9,600 bases, encoding a single polyprotein of approximately 3,000 amino acids, flanked by conserved 5Ј and 3Ј untranslated regions (UTRs). The viral polyprotein comprises four structural proteins followed by six nonstructural (NS) proteins that play essential roles in viral replication (25).One of the best-studied nonstructural proteins is NS3, a bifunctional protein that consists of an N-terminal protease domain and a C-terminal helicase domain (9). The protease domain has a trypsin-like fold with a flat and solvent-exposed substrate binding site (11,21). The central portion of the NS4A protein is integrated into the protein fold of the NS3 protease domain and is required for full activity (3). The NS3-NS4A (NS3 coexpressed with NS4A) protease plays a critical role in the maturation of the viral polyprotein precursor and was recognized early on as potential target for antiviral drugs (2). Indeed, the first direct acting antiviral agent to be studied in humans was the protease inhibitor BILN 2061, and two other protease inhibitors, telaprevir and boceprevir, are currently in phase III trials (10,1...

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“…Seliciclib demonstrated a higher area-under-the-curve (AUC), longer elimination half-life and better intratumoral drug delivery, when compared with the similar 2,6,9-tri-substituted purine Cdk inhibitors olomoucine and bohemine (Raynaud et al, 2004). Seliciclib is highly bound to plasma proteins (90%), primarily albumin (Vita et al, 2005). To characterise further the PK of this agent, a first in-human, single oral dose, volunteer study was undertaken in 12 healthy subjects, administering between 50 and 800 mg of seliciclib (De la Motte and Gianella-Borradori, 2004).…”

mentioning

confidence: 99%

A phase I trial of the selective oral cyclin-dependent kinase inhibitor seliciclib (CYC202; R-Roscovitine), administered twice daily for 7 days every 21 days

et al. 2006

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Seliciclib (CYC202; R-roscovitine) is the first selective, orally bioavailable inhibitor of cyclin-dependent kinases 1, 2, 7 and 9 to enter clinical trial. Preclinical studies showed antitumour activity in a broad range of human tumour xenografts. A phase I trial was performed with a 7-day b.i.d. p.o. schedule. Twenty-one patients (median age 62 years, range: 39 -73 years) were treated with doses of 100, 200 and 800 b.i.d. Dose-limiting toxicities were seen at 800 mg b.i.d.; grade 3 fatigue, grade 3 skin rash, grade 3 hyponatraemia and grade 4 hypokalaemia. Other toxicities included reversible raised creatinine (grade 2), reversible grade 3 abnormal liver function and grade 2 emesis. An 800 mg portion was investigated further in 12 patients, three of whom had MAG3 renograms. One patient with a rapid increase in creatinine on day 3 had a reversible fall in renal perfusion, with full recovery by day 14, and no changes suggestive of renal tubular damage. Further dose escalation was precluded by hypokalaemia. Seliciclib reached peak plasma concentrations between 1 and 4 h and elimination half-life was 2 -5 h. Inhibition of retinoblastoma protein phosphorylation was not demonstrated in peripheral blood mononuclear cells. No objective tumour responses were noted, but disease stabilisation was recorded in eight patients; this lasted for a total of six courses (18 weeks) in a patient with ovarian cancer.

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Stability, pKa and plasma protein binding of roscovitine

Cited by 49 publications

References 36 publications

Exposure to Total and Protein-Unbound Rifampin Is Not Affected by Malnutrition in Indonesian Tuberculosis Patients

Exposure to Total and Protein-Unbound Rifampin Is Not Affected by Malnutrition in Indonesian Tuberculosis Patients

Preclinical Characterization of BI 201335, a C-Terminal Carboxylic Acid Inhibitor of the Hepatitis C Virus NS3-NS4A Protease

A phase I trial of the selective oral cyclin-dependent kinase inhibitor seliciclib (CYC202; R-Roscovitine), administered twice daily for 7 days every 21 days

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