Stable Isotope Methodology for Kinetic Studies of Interconversion of Cortisol and Cortisone in a Human Subject

Kasuya, Yasuji; Ishimaru, Hiromasa; Shibasaki, Hiromi; Furuta, Takahisa

doi:10.1016/s0039-128x(97)00102-5

Cited by 16 publications

(10 citation statements)

References 31 publications

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“…C4]cortisone (data not shown). These observations were entirely consistent with those previously reported by Kasuya et al [14]. Treatment of subjects with MK-0916 lowered concentrations of plasma [ 13 C4]cortisol in a dose-dependent manner without any apparent effect on the relative time course over which plasma Table 4 Mean (SD) plasma pharmacokinetic parameters for MK-0916 in healthy male subjects given once-daily doses for 14 days (the multiple-dose study; all n = 6) Figure 5).…”

Section: Fit Of the Pharmacokinetic Data To A Two-compartment Saturabsupporting

confidence: 94%

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: Fit Of the Pharmacokinetic Data To A Two-compartment Saturabsupporting

confidence: 94%

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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“…Three healthy adult subjects (subject A, aged 25 years, male, 68 kg in weight; subject B, aged 23 years, male, 57 kg; and subject C, aged 25 years, male, 65 kg) participated in this study. The subjects received a single 5-mg oral dose of cortisol-d 5 (subjects A and B) or a single 3-mg oral dose of cortisol-13 C 4 (subject C) in the morning (at 10:00 AM) after 12 h of overnight fasting (Kasuya et al, 1998(Kasuya et al, , 2002. No individual was receiving any medication.…”

Section: Methodsmentioning

confidence: 99%

EVIDENCE FOR THE VALIDITY OF CORTISOL 6β-Hydroxylation CLEARANCE AS a NEW INDEX FOR IN VIVO CYTOCHROME P450 3A PHENOTYPING IN HUMANS

Furuta

Suzuki²,

Mori³

et al. 2003

Drug Metab Dispos

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This article is available online at http://dmd.aspetjournals.org ABSTRACT:This study uses stable isotope methodology to evaluate the validity of 6␤-hydroxylation clearance of endogenous cortisol as a new index for in vivo CYP3A phenotyping in humans. Important factors contradictory to the use of a conventional index of urinary ratio of 6␤-hydroxycortisol to cortisol (6␤-OHF/F) to evaluate in vivo CYP3A activity are also discussed. Stable isotopically labeled cortisol (3-5 mg) was orally administered to three healthy adult subjects to accurately determine the fractional metabolic clearance specific for the 6␤-hydroxylation of cortisol. Plasma concentrations of labeled cortisol and urinary excreted amounts of labeled cortisol and 6␤-OHF were analyzed by gas chromatography-mass spectrometry simultaneously with their endogenous counterparts. There was a good correlation between endogenous and exogenous 6␤-hydroxylation clearances in the three subjects tested (r ‫؍‬

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“…After oxidative cleavage of the A-ring to give enol lactone 10, two carbon-13 atoms could be introduced as an acetyl group followed by reconstruction of the A-ring to give [3,4-13 C 2 ,1a-2 H]cortisone-BMD (9). The second deuterium atom could then be introduced via dehydrogenation to introduce a 6,7-double bond and subsequent regioselective catalytic deuteration.…”

Section: Resultsmentioning

confidence: 99%

A gram‐scale synthesis of [3,4‐¹³C_2,1α,7‐²H₂]cortisone

Heffner

Gong

2011

Labelled Comp Radiopharmac

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A gram-scale synthesis of [3,[4][5][6][7][8][9][10][11][12][13] C 2 ,1a,7-2 H 2 ]cortisone from prednisone was developed. The deuterium atom at the C-1 position was introduced through a regioselective and stereoselective deuteration of the 1,2-double bond of the 1,4-diene-3-one using Wilkinson's catalyst. After the oxidative cleavage of the A-ring, two carbon-13 atoms were introduced via acetylation of an A-ring enol lactone with [1,[2][3][4][5][6][7][8][9][10][11][12][13] C 2 ]acetyl chloride. The steroidal A-ring was then reconstructed to incorporate the carbon-13 atoms into the C-3 and C-4 positions. The deuterium atom at C-7 was introduced through a regioselective deuteration of the 6,7-double bond of a 4,6-diene-3-one intermediate using palladium on strontium carbonate. The M + 4 stable isotope labeled cortisone was thus prepared in ca. 4% overall yield. In addition, [3,[4][5][6][7][8][9][10][11][12][13]

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Stable Isotope Methodology for Kinetic Studies of Interconversion of Cortisol and Cortisone in a Human Subject

Cited by 16 publications

References 31 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

EVIDENCE FOR THE VALIDITY OF CORTISOL 6β-Hydroxylation CLEARANCE AS a NEW INDEX FOR IN VIVO CYTOCHROME P450 3A PHENOTYPING IN HUMANS

A gram‐scale synthesis of [3,4‐¹³C_2,1α,7‐²H₂]cortisone

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Stable Isotope Methodology for Kinetic Studies of Interconversion of Cortisol and Cortisone in a Human Subject

Cited by 16 publications

References 31 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

EVIDENCE FOR THE VALIDITY OF CORTISOL 6β-Hydroxylation CLEARANCE AS a NEW INDEX FOR IN VIVO CYTOCHROME P450 3A PHENOTYPING IN HUMANS

A gram‐scale synthesis of [3,4‐13C2,1α,7‐2H2]cortisone

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A gram‐scale synthesis of [3,4‐¹³C_2,1α,7‐²H₂]cortisone