Plasma-Pooling Methods To Increase Throughput for in Vivo Pharmacokinetic Screening

Hop, Cornelis E. C. A.; Wang, Zhen; Chen, Qing; Kwei, Gloria Y.

doi:10.1021/js970486q

Cited by 218 publications

(134 citation statements)

References 7 publications

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“…Samples from each subject collected at 0, 0.5, 1, 2, 3, 4, 5, and 6 h were thawed at room temperature. Appropriate aliquots from each sample were pooled such that the pooled sample had a concentration proportional to the pharmacokinetic area under the curve (AUC 0 -6 h ) for a total volume of 1 to 3 ml of plasma (Hop et al, 1998). The pooled plasma samples were extracted using solid-phase extraction cartridges (Oasis HLB, 3 ml; Waters, Milford, MA).…”

Section: Chemicals [mentioning

confidence: 99%

Metabolism and Disposition in Humans of Raltegravir (MK-0518), an Anti-AIDS Drug Targeting the Human Immunodeficiency Virus 1 Integrase Enzyme

Kassahun

McIntosh²,

Cui³

et al. 2007

Drug Metab Dispos

265

220

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ABSTRACT:Raltegravir is a potent human immunodeficiency virus 1 (HIV-1) integrase strand transfer inhibitor that is being developed as a novel anti-AIDS drug. The absorption, metabolism, and excretion of raltegravir were studied in healthy volunteers after a single oral dose of 200 mg (200 Ci) of [ 14 C]raltegravir. Plasma, urine, and fecal samples were collected at specified intervals up to 240 h postdose, and the samples were analyzed for total radioactivity, parent compound, and metabolites. Radioactivity was eliminated in substantial amounts in both urine (32%) and feces (51%). The elimination of radioactivity was rapid, since the majority of the recovered dose was attributable to samples collected through 24 h. In extracts of urine, two components were detected and were identified as raltegravir and the glucuronide of raltegravir (M2), and each accounted for 9% and 23% of the dose recovered in urine, respectively. Only a single radioactive peak, which was identified as raltegravir, was detected in fecal extracts; raltegravir in feces is believed to be derived, at least in part, from the hydrolysis of M2 secreted in bile, as demonstrated in rats. The major entity in plasma was raltegravir, which represented 70% of the total radioactivity, with the remaining radioactivity accounted for by M2. Studies using cDNA-expressed UDP-glucuronosyltransferases (UGTs), form-selective chemical inhibitors, and correlation analysis indicated that UGT1A1 was the main UGT isoform responsible for the formation of M2. Collectively, the data indicate that the major mechanism of clearance of raltegravir in humans is UGT1A1-mediated glucuronidation.HIV-1 is the etiologic agent of AIDS. HIV infection continues to be a major problem with more than 40 million individuals currently infected with the virus worldwide ([UNAIDS] Joint United Nations Programme on HIV/AIDS 2006 Report on the global AIDS epidemic. http://www.unaids.org). The current standard of care for treating HIV infection, called HAART, is a regimen typically consisting of three or more drugs from two or more available classes. Current HAART medications (of which there are Ͼ20) include members from four classes of drugs: nucleoside reverse transcriptase inhibitors, nonnucleoside reverse transcriptase inhibitors, protease inhibitors, and fusion inhibitors. Although the advent of HAART has significantly reduced AIDS-related morbidity and mortality, it has been estimated that 78% of treatment-naive patients harbor viruses that are resistant to one or more of the three classes (nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, and protease inhibitors) (Richman, 2001;Little et al., 2002). Because of this factor and issues of tolerability, toxicity, and patient noncompliance due to the rigorous drug administration schedules, there is a critical need for new HIV therapies capable of addressing the deficiencies inherent with currently used drugs.Integrase is one of the three HIV-1 enzymes required for viral replication (Esposito and Cr...

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Section: Chemicals [mentioning

confidence: 99%

Metabolism and Disposition in Humans of Raltegravir (MK-0518), an Anti-AIDS Drug Targeting the Human Immunodeficiency Virus 1 Integrase Enzyme

Kassahun

McIntosh²,

Cui³

et al. 2007

Drug Metab Dispos

265

220

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“…Aliquots of plasma from 8 subjects were pooled (0-24 hours) in a time and volume dependent manner [17], to generate a sample representative of an area under the curve (AUC) exposure for parent and metabolites after Day 1 and Day 14. Aliquots of these 2 samples (60ml) were treated with 3 volumes of acetonitrile and vortex mixed (3min).…”

Section: Preparation and Extraction Of Human Plasma For Metabolite Idmentioning

confidence: 99%

“…Female rabbit plasma samples (0.25-24hr) were obtained from a dose range finding study where the highest tolerated dose was 60mg/kg/day. Aliquots of plasma were pooled in a time and volume dependent manner [17], to generate a sample, for each species, representative of an area under the curve (AUC) exposure for parent and metabolites. Pooled control plasma for human and preclinical species was supplied by GlaxoSmithKline Spa, Verona, Italy.…”

Section: Preparation and Extraction Of Clinical And Preclinical Plasmmentioning

confidence: 99%

Metabolites in Safety Testing: Issues and Approaches to the Safety Evaluation of Human Metabolites in a Drug that is Extensively Metabolized

Griffini¹,

Àlex

James³

et al. 2010

J Drug Metabol Toxicol

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“…An alternative strategy is to pool the samples collected at each consecutive time point from a single animal dosed with an individual compound to produce a single sample for analysis (34,35). The concentration of this pooled sample is then multiplied by the time period of collection to give an estimation of the area under the concentration versus time curve (AUC).…”

Section: Dmpk In Drug Discoverymentioning

confidence: 99%

The application of cassette dosing for pharmacokinetic screening in small-molecule cancer drug discovery

Smith

Raynaud

Workman

2007

Molecular Cancer Therapeutics

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Pharmacokinetic evaluation is an essential component of drug discovery and should be conducted early in the process so that those compounds with the best chance of success are prioritized and progressed. However, pharmacokinetic analysis has become a serious bottleneck during the 'hit-to-lead' and lead optimization phases due to the availability of new targets and the large numbers of compounds resulting from advances in synthesis and screening technologies. Cassette dosing, which involves the simultaneous administration of several compounds to a single animal followed by rapid sample analysis by liquid chromatography/tandem mass spectrometry, was developed to increase the throughput of in vivo pharmacokinetic screening. Although cassette dosing is advantageous in terms of resources and throughput, there are possible complications associated with this approach, such as the potential for compound interactions. Following an overview of the cassette dosing literature, this article focuses on the application of the technique in anticancer drug discovery. Specific examples are discussed, including the evaluation of cassette dosing to assess pharmacokinetic properties in the development of cyclin-dependent kinase and heat shock protein 90 inhibitors. Subject to critical analysis and validation in each case, the use of cassette dosing is recommended in appropriate chemical series to enhance the efficiency of drug discovery and reduce animal usage. [Mol Cancer Ther 2007;6(2):428 -40]

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Plasma-Pooling Methods To Increase Throughput for in Vivo Pharmacokinetic Screening

Cited by 218 publications

References 7 publications

Metabolism and Disposition in Humans of Raltegravir (MK-0518), an Anti-AIDS Drug Targeting the Human Immunodeficiency Virus 1 Integrase Enzyme

Metabolism and Disposition in Humans of Raltegravir (MK-0518), an Anti-AIDS Drug Targeting the Human Immunodeficiency Virus 1 Integrase Enzyme

Metabolites in Safety Testing: Issues and Approaches to the Safety Evaluation of Human Metabolites in a Drug that is Extensively Metabolized

The application of cassette dosing for pharmacokinetic screening in small-molecule cancer drug discovery

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