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

Taft, David R.; Nordt, Sean Patrick; Iyer, Ganesh; Schwenk, Michael H.

doi:10.1002/(sici)1099-081x(199809)19:6<373::aid-bdd113>3.0.co;2-t

Cited by 7 publications

(4 citation statements)

References 20 publications

(25 reference statements)

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“…Indeed, methazolamide showed a similarly long t 1/2 . 17 For CG100649, summary concentration ratios between whole blood and plasma remained considerable stable throughout the dosing interval ( Figure 3A).…”

Section: Discussionmentioning

confidence: 95%

GCG100649, A Novel Cyclooxygenase‐2 Inhibitor, Exhibits a Drug Disposition Profile in Healthy Volunteers Compatible With High Affinity to Carbonic Anhydrase‐I/II: Preliminary Dose–Exposure Relationships to Define Clinical Development Strategies

Hirankarn

Barrett

Alamuddin

et al. 2013

Clinical Pharm in Drug Dev

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CG100649, proposed as a dual inhibitor of cyclooxygenase (COX)-2 and carbonic anhydrase (CA)-I/-II, is long-lived in plasma and whole blood. The mean ± SD half-lives were 131 ± 19 and 127 ± 33 hours, respectively, after administration of oral single doses of 2 or 8 mg CG100649 to healthy volunteers. The whole blood to plasma concentration ratio (78 ± 23) for CG100649 is linear over the dosing interval reflecting a biodistribution pattern consistent with other strong CA-inhibitors (e.g., acetazolamide, methazolamide). A one compartment model with first order absorption and elimination described CG100649 concentration-time profiles well. Estimates (%relative SD) between plasma and whole blood were in agreement for the absorption rate constant, 1.54 (58.6) and 1.43 (28.0) hour(-1) , respectively, but considerably different for clearance, 3.29 (10.4) and 0.04 (7.7) L/h/70 kg, and for volume of distribution, 559 (6.7) and 7.6 (2.4) L/70 kg, respectively. The extent to which these unique PK characteristics of CG100649 discriminate it from other COX-2 inhibitors will be the subject of future investigation.

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Section: Discussionmentioning

confidence: 95%

GCG100649, A Novel Cyclooxygenase‐2 Inhibitor, Exhibits a Drug Disposition Profile in Healthy Volunteers Compatible With High Affinity to Carbonic Anhydrase‐I/II: Preliminary Dose–Exposure Relationships to Define Clinical Development Strategies

Hirankarn

Barrett

Alamuddin

et al. 2013

Clinical Pharm in Drug Dev

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“…To develop the PK model, we adapted and modified a previously described model that adequately described VEN and O‐desmethylvenlafaxine concentrations in healthy young men (mean (SD) age: 26 (3) years old) using the first‐order conditional estimation model with interaction 8 . This model accounts for the first‐pass metabolism of VEN to O‐desmethylvenlafaxine via CYP2D6 and consists of three transit compartments for absorption and one compartment for elimination ( Figure ) 8,17,18 . In accordance with previously published similar models, we fixed the volume of distribution of O‐desmethylvenlafaxine at 210 L, the hepatic plasma flow at 0.63 L/h*bodyweight (in kilograms), and the volume of the liver compartment to 1 L 8,17 .…”

Section: Methodsmentioning

confidence: 99%

“…8 This model accounts for the firstpass metabolism of VEN to O-desmethylvenlafaxine via CYP2D6 and consists of three transit compartments for absorption and one compartment for elimination (Figure S2). 8,17,18 In accordance with previously published similar models, we fixed the volume of distribution of O-desmethylvenlafaxine at 210 L, the hepatic plasma flow at University, St. Louis, Missouri, USA; 9 Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania, USA; 10 Clinical Laboratory and Diagnostic Services, Centre for Addiction and Mental Health, Toronto, Ontario, Canada; 11 Division of Research in Patient Services, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA. *Correspondence: Daniel J. Müller (daniel.mueller@camh.ca) † The first two authors contributed equally to the work; the last two ("senior") authors contributed equally to the work; except for the first three authors and the last three authors, all authors contributed equally and are listed in alphabetical order.…”

Section: Population Pharmacokinetic Modelmentioning

confidence: 99%

CYP2D6 Phenotype Influences Pharmacokinetic Parameters of Venlafaxine: Results from a Population Pharmacokinetic Model in Older Adults with Depression

Men,

Taylor,

Marshe

et al. 2024

Clin Pharma and Therapeutics

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In this study, we aimed to improve upon a published population pharmacokinetic (PK) model for venlafaxine (VEN) in the treatment of depression in older adults, then investigate whether CYP2D6 metabolizer status affected model‐estimated PK parameters of VEN and its active metabolite O‐desmethylvenlafaxine. The model included 325 participants from a clinical trial in which older adults with depression were treated with open‐label VEN (maximum 300 mg/day) for 12 weeks and plasma levels of VEN and O‐desmethylvenlafaxine were assessed at weeks 4 and 12. We fitted a nonlinear mixed‐effect PK model using NONMEM to estimate PK parameters for VEN and O‐desmethylvenlafaxine adjusted for CYP2D6 metabolizer status and age. At both lower doses (up to 150 mg/day) and higher doses (up to 300 mg/day), CYP2D6 metabolizers impacted PK model‐estimated VEN clearance, VEN exposure, and active moiety (VEN + O‐desmethylvenlafaxine) exposure. Specifically, compared with CYP2D6 normal metabolizers, (i) CYP2D6 ultra‐rapid metabolizers had higher VEN clearance; (ii) CYP2D6 intermediate metabolizers had lower VEN clearance; (iii) CYP2D6 poor metabolizers had lower VEN clearance, higher VEN exposure, and higher active moiety exposure. Overall, our study showed that including a pharmacogenetic factor in a population PK model could increase model fit, and this improved model demonstrated how CYP2D6 metabolizer status affected VEN‐related PK parameters, highlighting the importance of genetic factors in personalized medicine.

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“…However, to avoid extensive extra experimental work (e.g. preparation of drug stock and reagent solutions) and due to the difficulty in finding drug plasma sequestration ratios, the selection of drug components were limited to on-going studies in our laboratory and it was random with the exception of indapamide and methazolamide, which were deliberately chosen due to their relatively high affinity to erythrocytes [10,11,14,15].…”

Section: Selection Of Drug Compoundsmentioning

confidence: 99%

Impact of hemolysis during sample collection: How different is drug concentration in hemolyzed plasma from that of normal plasma?

Tan¹,

Gagné²,

Lévesque³

et al. 2012

Journal of Chromatography B

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

Cited by 7 publications

References 20 publications

GCG100649, A Novel Cyclooxygenase‐2 Inhibitor, Exhibits a Drug Disposition Profile in Healthy Volunteers Compatible With High Affinity to Carbonic Anhydrase‐I/II: Preliminary Dose–Exposure Relationships to Define Clinical Development Strategies

GCG100649, A Novel Cyclooxygenase‐2 Inhibitor, Exhibits a Drug Disposition Profile in Healthy Volunteers Compatible With High Affinity to Carbonic Anhydrase‐I/II: Preliminary Dose–Exposure Relationships to Define Clinical Development Strategies

CYP2D6 Phenotype Influences Pharmacokinetic Parameters of Venlafaxine: Results from a Population Pharmacokinetic Model in Older Adults with Depression

Impact of hemolysis during sample collection: How different is drug concentration in hemolyzed plasma from that of normal plasma?

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