An in vivo microdialysis coupled with liquid chromatography/tandem mass spectrometry study of cortisol metabolism in monkey adipose tissue

Sun, Li; Stenken, Julie A.; Brunner, John; Michel, Kimberly; Adelsberger, Jennifer K.; Yang, Amy Y.; Zhao, Jamie J.; Musson, Donald G.

doi:10.1016/j.ab.2008.06.036

Cited by 16 publications

(21 citation statements)

References 41 publications

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“…13 C4]cortisone and [ 13 C4]cortisol content as previously described [17][18][19]. Androstenedione, DHEA and DHEA-S concentrations were analysed by Bioanalytical Research Corporation (Gent, Belgium).…”

Section: Bioanalytical Methodsmentioning

confidence: 99%

“…These subjects had not taken any medications (prescription or nonprescription) for 2 weeks prior to the study and did not anticipate any need for medication during the study. C4]cortisone was Ն99% as determined by high-pressure liquid chromatography with ultraviolet detection and nuclear magnetic resonance for 13 C [17].…”

Section: Subjectsmentioning

confidence: 99%

“…In prior studies, activity of 11b-HSD1 has been characterized in liver microsomes from dogs, monkeys and humans by microdialysis coupled with stable-isotope methodology [19]. It has also been studied in vivo in the serum and ex vivo in specific organs of interest using stable-isotope methodology in mice [23], by in vivo microdialysis in superficial adipose tissue in the monkey [17], and by ex vivo assay in a clinical C4]cortisone acetate.The data are from subjects dosed with 0.20-50 mg MK-0916 once daily for 14 days. Inhibition of 11b-HSD1 was assessed on the first and 14th days of dosing, and 6 days after the last dose.The superimposed curve indicates the best fit to a simple Emax model.…”

Section: Figurementioning

confidence: 99%

“…All doses of [ 13 C4]cortisone acetate were given approximately 9 h after doses of MK-0916 and at approximately the same (Ϯ30 min) time of day within any given subject. Plasma samples were collected at times 0 (predose), 15 These pharmacodynamic evaluations were performed on day -1 (within 72 h prior to the first dose of MK-0916) and three subsequent days, namely days 1, 14 and 20 for subjects in panels A, E, F, G and I, and days 1, 28 and 34 for subjects in panels B, C, D and J (because these subjects received MK-0916 daily on days [15][16][17][18][19][20][21][22][23][24][25][26][27][28].This yielded assessments at baseline, on the first and 14th days during multiple dosing, and 6 days after the last dose. The primary end-point was the ratio between the area under the curve (AUC) from 0-4 h (AUC0-4h) for plasma [ 13 C4]cortisol on the 14th day of continuous MK-0916 dosing (day 14 in panels A, E, F, G and I, and day 28 in panels B, C and D) and the corresponding AUC0-4h at baseline (on day -1).…”

Section: Procedures In the Multiple-dose Studymentioning

confidence: 99%

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Pharmacokinetic–pharmacodynamic studies of the 11β‐hydroxysteroid dehydrogenase type 1 inhibitor MK‐0916 in healthy subjects

Wright

Stone

Crumley

et al. 2013

Brit J Clinical Pharma

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AIMSTo characterize pharmacokinetic parameters of MK-0916 and its safety and tolerability in lean, healthy male subjects following single and multiple oral doses. To assess (by stable-isotope labelling) the in vivo inhibition of cortisone-to-cortisol conversion following oral MK-0916. METHODSData are presented from two randomized, controlled, double-blind, rising-dose phase I studies. In the first study, subjects received single oral doses of 0.4-100 mg MK-0916 (n = 16). In the second study, subjects received 0.2-225 mg MK-0916 followed by daily doses of 0.2-100 mg for 13 days beginning on day 2 or day 15 (n = 80). Plasma and urine drug concentrations were measured for pharmacokinetic analysis. For pharmacodynamic analysis, concentrations of plasma [13 C4]cortisol were measured by high-pressure liquid chromatography and tandem mass spectrometry following a single oral dose of 5 mg [ 13 C4]cortisone. RESULTSDoses Ն3 mg were rapidly absorbed (time at which maximal concentration was achieved in plasma, 1.1-1.8 h). Exposure (measured as the area under the concentration-time curve from 0 to 168 h) increased approximately in proportion to dose. Values for the maximal plasma concentration and the plasma concentration at 24 h increased in excess of dose proportionality at doses <6 mg and roughly in proportion to dose at doses >6 mg. In subjects dosed with 6 mg MK-0916 once daily for 14 days, the mean trough plasma concentration was 240 nM and in vivo cortisone-to-cortisol conversion was inhibited by 84%. The relationship between plasma MK-0916 and hepatic 11b-hydroxysteroid dehydrogenase type 1 inhibition was well represented by a simple Emax model with an IC50 of 70.4 nM. Exposure to MK-0916 was generally well tolerated. CONCLUSIONSThese findings indicate that 11b-hydroxysteroid dehydrogenase type 1 is effectively inhibited in human subjects by doses of MK-0916 that are well tolerated. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• The intracellular enzyme 11b-hydroxysteroid dehydrogenase type 1 converts the inactive glucocorticoid cortisone into the active hormone cortisol in many tissues, including the liver and adipocytes. It is thought that increased conversion of cortisone to cortisol contributes to pathophysiology associated with the metabolic syndrome.• MK-0916 is an inhibitor of 11b-hydroxysteroid dehydrogenase type 1 that has been evaluated clinically as a potential therapy for type 2 diabetes, obesity or hypertension. WHAT THIS STUDY ADDS• In lean, healthy male subjects, MK-0916 was well tolerated when given in oral doses that were sufficient to provide profound inhibition of hepatic conversion of cortisone to cortisol.• Multiple-dose administration of 6 mg day -1 MK-0916 provided mean plasma concentrations >200 nM at all times, a plasma drug concentration that inhibited systemic 11b-hydroxysteroid dehydrogenase type 1 by 84%.

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Section: Bioanalytical Methodsmentioning

confidence: 99%

Section: Subjectsmentioning

confidence: 99%

Section: Figurementioning

confidence: 99%

Section: Procedures In the Multiple-dose Studymentioning

confidence: 99%

See 2 more Smart Citations

Pharmacokinetic–pharmacodynamic studies of the 11β‐hydroxysteroid dehydrogenase type 1 inhibitor MK‐0916 in healthy subjects

Wright

Stone

Crumley

et al. 2013

Brit J Clinical Pharma

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“…Most animal studies of retrodialysis have been performed for studies of inflammation in rodents but also in studies of lipolysis and drug metabolism [34,35]. Examples of applications of skin retrodialysis in animal research are provided below and listed in table 1.…”

Section: Retrodialysis In Animal Studiesmentioning

confidence: 99%

Retrodialysis: A Review of Experimental and Clinical Applications of Reverse Microdialysis in the Skin

Melgaard

Hersini

Gazerani

et al. 2013

Skin Pharmacol Physiol

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Microdialysis is a method that has been used for decades to recover endogenous mediators, metabolites and drugs from the interstitial space in several tissues of both animals and humans. The principle of microdialysis is the flux of compounds across a semipermeable membrane. The application of microdialysis as a method of drug delivery is a process referred to as retrodialysis, i.e. the introduction of a substance into the extracellular space via a microdialysis probe. Thus, microdialysis also offers opportunities to deliver mediators and drugs to target tissues by adding solutes to the perfusion medium. In this context, retrodialysis combines a method for minimally invasive delivery with a sampling method to study biological processes in health and disease. The aim of this review is to give insight into the use of retrodialysis by outlining examples of retrodialysis studies focusing on applications in skin in animal studies, human experimental investigations and clinical settings.

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Current separation and detection methods in microdialysis the drive towards sensitivity and speed

Guihen

O’Connor

2009

Electrophoresis

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This review outlines some of the analytical challenges associated with the analysis of microdialysis (MD) samples, in particular, the minute complex sample volumes that are often encountered. In MD sampling many different low-molecular-weight molecules can be collected, but the research findings are often limited by the sensitivity, specificity, and reliability of the analytical technique that is coupled to the dialysis probe. Therefore it is critical that a lot of consideration is given in selecting the most suitable analytical method including the most appropriate detector. This review aims to highlight the strengths and weaknesses of a range of commonly used analytical methods employed in MD. In Section 1, a brief overview of the MD technique is described, followed by a discussion on some of the advantages and drawbacks of this sampling technique. Sections 2 and 3 examine analytical and other technical considerations regarding analysis, with special emphasis on the factors that specifically influence analytical detection. Section 4 outlines the most commonly employed analytical techniques used in MD, including HPLC coupled with various detectors. Detail is given regarding the LOD and LOQ for many applications using each detector. As MS is of such high importance in MD, a special sub-section has been devoted to it. The importance of CE is also highlighted, with specific applications described. In addition, analytical techniques that do not appear to have found routine use in MD are discussed. Section 5 is concerned with recent innovations in chemical separation techniques, in particular MCE and ultra-performance liquid chromatography. Specific applications of the coupling of these techniques with MD are highlighted, along with technical challenges associated with miniaturization. In the Section 6, the future outlook of MD is discussed. Techniques other than electrophoretic- and chromatographic based separation methods are outside the scope of this review.

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An in vivo microdialysis coupled with liquid chromatography/tandem mass spectrometry study of cortisol metabolism in monkey adipose tissue

Cited by 16 publications

References 41 publications

Pharmacokinetic–pharmacodynamic studies of the 11β‐hydroxysteroid dehydrogenase type 1 inhibitor MK‐0916 in healthy subjects

Pharmacokinetic–pharmacodynamic studies of the 11β‐hydroxysteroid dehydrogenase type 1 inhibitor MK‐0916 in healthy subjects

Retrodialysis: A Review of Experimental and Clinical Applications of Reverse Microdialysis in the Skin

Current separation and detection methods in microdialysis the drive towards sensitivity and speed

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