Time Course and Disposition of Methazolamide in Human Plasma and Red Blood Cells

Bayne, W.F.; Tao, F.T.; Rogers, G. G.; Chu, L.‐C.; Theeuwes, Felix

doi:10.1002/jps.2600700115

Cited by 21 publications

(16 citation statements)

References 14 publications

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“…Bayne studied the plasma and RBC disposition of MTZ in human subjects. MTZ plasma concentrations declined with an apparent half-life of 7.5 h and urinary recovery of unchanged drug was 25% [12]. However, this study was limited to only three subjects, two of which received a different oral dose (50 and 150 mg) and one subject who was placed on a multiple dose regimen.…”

Section: Resultsmentioning

confidence: 97%

“…Erythrocyte MTZ concentrations greatly exceeded those measured in plasma. Extensive erythrocyte uptake has previously been demonstrated for MTZ [11,12] and other CAIs such as ACZ [15,16] and dorzolamide [17].…”

Section: Resultsmentioning

confidence: 99%

“…Since MTZ readily distributes into and is sequestered by erythrocytes, plasma clearance of MTZ is significantly influenced by RBC distribution and is a poor indicator of total body clearance. Bayne attempted to estimate the total body clearance of MTZ from plasma by subtracting from the dose the estimated amount of drug remaining in the erythrocytes and dividing that value by AUC [12]. In the present study, whole blood was utilized as the reference fluid.…”

Section: Resultsmentioning

confidence: 99%

“…Overall, the model contained six parameters: k 10 , k 12 , k 21 , k a , V c and f r (fraction of drug excreted unchanged by kidney). Assuming that the administered dose was completely absorbed [11,12], the following differential equations were utilized:…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, information is limited regarding the disposition of MTZ in healthy subjects. Previous investigators have characterized the disposition of MTZ in plasma [11,12]. Being a CAI, MTZ would be expected to distribute into and be sequestered by red blood cells (RBCs).…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

Blood disposition and urinary excretion kinetics of methazolamide following oral administration to human subjects

Taft

Nordt

Iyer

et al. 1998

Biopharm. Drug Dispos.

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Section: Resultsmentioning

confidence: 97%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Blood disposition and urinary excretion kinetics of methazolamide following oral administration to human subjects

Taft

Nordt

Iyer

et al. 1998

Biopharm. Drug Dispos.

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Effects of low temperature on blood‐to‐plasma ratio measurement

Novak

Burchett

2021

Biopharm & Drug Disp

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The blood-to-plasma ratio (R b ) is an important property of drug candidates. R b is applied widely in drug discovery to convert plasma pharmacokinetic parameters to the respective parameters in blood and to develop in vitro-in vivo correlations. Some compounds such as prodrugs, soft drugs, and peptide mimetics are unstable in blood, making accurate in vitro R b measurement challenging, but necessary. Low temperature often reduces the rate of enzymatic and chemical reactions and increases the stability of labile compounds in biomatrices. In this study, the effects of 4°C on R b measurement were evaluated using a set of structurally diverse compounds with various binding and red blood cell (RBC) transport mechanisms. The results indicate that a 4°C R b method provides comparable R b values to the 37°C method for most compounds and can therefore be applied to measure the R b of unstable compounds in drug discovery. In some rare cases, when compounds have a high affinity to specific RBC components (e.g., carbonic anhydrase), the 4°C method may underestimate R b. In these specific cases, the use of appropriate inhibitors to stabilize unstable compounds is recommended.

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The Lab Oddity Prevails: Discovery of Pan‐CDK Inhibitor (R)‐S‐Cyclopropyl‐S‐(4‐{[4‐{[(1R,2R)‐2‐hydroxy‐1‐methylpropyl]oxy}‐5‐(trifluoromethyl)pyrimidin‐2‐yl]amino}phenyl)sulfoximide (BAY 1000394) for the Treatment of Cancer

et al. 2013

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Lead optimization of a high-throughput screening hit led to the rapid identification of aminopyrimidine ZK 304709, a multitargeted CDK and VEGF-R inhibitor that displayed a promising preclinical profile. Nevertheless, ZK 304709 failed in phase I studies due to dose-limited absorption and high inter-patient variability, which was attributed to limited aqueous solubility and off-target activity against carbonic anhydrases. Further lead optimization efforts to address the off-target activity profile finally resulted in the introduction of a sulfoximine group, which is still a rather unusual approach in medicinal chemistry. However, the sulfoximine series of compounds quickly revealed very interesting properties, culminating in the identification of the nanomolar pan-CDK inhibitor BAY 1000394, which is currently being investigated in phase I clinical trials.

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Time Course and Disposition of Methazolamide in Human Plasma and Red Blood Cells

Cited by 21 publications

References 14 publications

Blood disposition and urinary excretion kinetics of methazolamide following oral administration to human subjects

Blood disposition and urinary excretion kinetics of methazolamide following oral administration to human subjects

Effects of low temperature on blood‐to‐plasma ratio measurement

The Lab Oddity Prevails: Discovery of Pan‐CDK Inhibitor (R)‐S‐Cyclopropyl‐S‐(4‐{[4‐{[(1R,2R)‐2‐hydroxy‐1‐methylpropyl]oxy}‐5‐(trifluoromethyl)pyrimidin‐2‐yl]amino}phenyl)sulfoximide (BAY 1000394) for the Treatment of Cancer

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