Disposition and metabolism of a new steroidal anti-inflammatory agent, deflazacort, in cynomolgus monkeys

Assandri, Alessandro; Ferrari, Pietro; Perazzi, A; Ripamonti, A.; Tuan, G.; Zerilli, L. F.

doi:10.3109/00498258309052253

Cited by 9 publications

(10 citation statements)

References 20 publications

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“…Although, 6α-hydroxylation was not previously demonstrated for BUD, 6α-hydroxy-metabolites have been described for other glucocorticosteroids. For deflazacort, 6α-hydroxymetabolite was detected as minor metabolite, while 6β-hydroxy-metabolite was the major metabolite in urine of cynomolgus monkeys [39], and in vitro metabolism of dexamethasone in human liver also showed the presence of a 6α-hydroxy-metabolite [40].…”

Section: Metabolic Pathways Of Budmentioning

confidence: 99%

Identification of budesonide metabolites in human urine after oral administration

Matabosch¹,

Pozo²,

Pérez‐Mañá

et al. 2012

Anal Bioanal Chem

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Budesonide (BUD) is a glucocorticoid widely used for the treatment of asthma, rhinitis, and inflammatory bowel disease. Its use in sport competitions is prohibited when administered by oral, intravenous, intramuscular, or rectal routes. However, topical preparations are not prohibited. Strategies to discriminate between legal and forbidden administrations have to be developed by doping control laboratories. For this reason, metabolism of BUD has been re-evaluated using liquid chromatography-tandem mass spectrometry (LC-MS/MS) with different scan methods. Urine samples obtained after oral administration of 3 mg of BUD to two healthy volunteers have been analyzed for metabolite detection in free and glucuronide metabolic fractions. Structures of the metabolites have been studied by LC-MS/MS using collision induced dissociation and gas chromatography-mass spectrometry (GC/MS) in full scan mode with electron ionization. Combination of all structural information allowed the proposition of the most comprehensive picture for BUD metabolism in humans to this date. Overall, 16 metabolites including ten previously unreported compounds have been detected. The main metabolite is 16α-hydroxy-prednisolone resulting from the cleavage of the acetal group. Other metabolites without the acetal group have been identified such as those resulting from reduction of C20 carbonyl group, oxidation of the C11 hydroxyl group and reduction of the A ring. Metabolites maintaining the acetal group have also been identified, resulting from 6-hydroxylation (6α and 6β-hydroxy-budesonide), 23-hydroxylation, reduction of C6-C7, oxidation of the C11 hydroxyl group, and reduction of the C20 carbonyl group. Metabolites were mainly excreted in the free fraction. All of them were excreted in urine during the first 24 h after administration, and seven of them were still detected up to 48 h after administration for both volunteers.

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Section: Metabolic Pathways Of Budmentioning

confidence: 99%

Identification of budesonide metabolites in human urine after oral administration

Matabosch¹,

Pozo²,

Pérez‐Mañá

et al. 2012

Anal Bioanal Chem

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“…Another possibility is a species difference in drug metabolism. Conversion of the drug to the metabolite may also be more efficient in sheep than humans, although studies with other primates [19] have indicated that all labeled deflazacort was converted to metabolites, mainly the active desacetylated form (>80%). Desacetylation, the transformation required to convert deflazacort to 21-desacetylated deflazacort, is a common metabolic reaction demonstrated for several steroids.…”

Section: Discussionmentioning

confidence: 99%

“…Desacetylation, the transformation required to convert deflazacort to 21-desacetylated deflazacort, is a common metabolic reaction demonstrated for several steroids. Assandri et al [19] and Martinelli et al [20] found little difference between the metabolic and pharmacokinetic fate of deflazacort in rat, monkey, and man, and both groups found that the oxazoline ring of deflazacort is very stable under varied chemical conditions. Studies with rats, dogs, and humans showed some species variability in the half-life of radiolabeled deflazacort and in the rates of biliary and renal excretion [20,21].…”

Section: Discussionmentioning

confidence: 99%

Effects of prednisolone and deflazacort on osteocalcin metabolism in sheep

et al. 1993

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Glucocorticoids adversely affect bone and mineral metabolism through a number of mechanisms, including inhibition of bone formation. Deflazacort is a glucocorticoid which has been reported to be relatively "bone-sparing." We compared the effects in oophorectomized sheep of deflazacort and prednisolone on the metabolism of osteocalcin (OC), a marker of osteoblast function. An [125]OC infusion method was used to measure the OC plasma clearance rate (PCR) and OC plasma production rate (PPR). Six-day intravenous infusion of deflazacort and prednisolone (in the dose range 0.007-1.00 mg/hour) induced dose-dependent decreases in OC PPR which were of a similar pattern but significantly different magnitude (P < 0.02); deflazacort demonstrated a potency about 150% that of prednisolone. Both steroids decreased plasma OC levels on a dose-related basis but at the lower doses 0.05 mg/hour (P < 0.05) and 0.013 mg/hour (P < 0.0005), deflazacort caused greater decrements. OC PCR was significantly increased only by higher doses of deflazacort (1.00 mg/hour, 0.25 mg/hour; P < 0.05). Deflazacort and prednisolone increased both postabsorptive plasma glucose and plasma calcium levels, but there were no significant differences between their effects. We conclude that plasma OC levels and OC PPR in sheep were more sensitive to the effects of deflazacort than to prednisolone. At high doses, the depressive effect of deflazacort on plasma OC levels may have been due in part to an increased OC PCR which was not evident with prednisolone treatment. However, the agents appeared to have a similar dose-dependent hyperglycemic effect, and both caused a small dose-dependent increase in plasma calcium.(ABSTRACT TRUNCATED AT 250 WORDS)

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“…activity of 5.04 Ci/mol and radiochemical purity greater than 98%, as determined by liquid-scintillation counting after t.1.c. and autoradiography (Assandri et al 1985 b).…”

Section: Chemicalsmentioning

confidence: 99%

Metabolic pathways of the anti-hypertensive agent, N-(2,5-dimethyl-1H-pyrrol-1-yl)-6-(4-morpholinyl)-3-pyridazinamine hydrochloride. II: Studies in the dog

et al. 1985

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The metabolic fate of a new anti-hypertensive, 1-pyrrolyl-pyridazinamine, was studied in male Beagle dogs given both p.o. and i.v. doses of the 14C-labelled drug (1 mg/kg). The compound given as a single i.v. injection disappeared from the central compartment with a half-life of about 0.9 h. Plasma levels of total 14C were represented mostly by metabolites. Eight urinary metabolites designated as metabolites I, II and XI-XVI were purified and their structures assigned by means of u.v., i.r., n.m.r. and mass spectrometry. Quantitatively the primary metabolic attack involved the morpholine moiety of the molecule which undergoes oxidative opening. A minor pathway afforded the cleavage of the pyrrole followed by chemical rearrangements to form six-membered sidnone-like products or a triazole derivative. The major (XIII) and three minor metabolites were studied for their antihypertensive activity in rats and were shown to be inactive.

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Disposition and metabolism of a new steroidal anti-inflammatory agent, deflazacort, in cynomolgus monkeys

Cited by 9 publications

References 20 publications

Identification of budesonide metabolites in human urine after oral administration

Identification of budesonide metabolites in human urine after oral administration

Effects of prednisolone and deflazacort on osteocalcin metabolism in sheep

Metabolic pathways of the anti-hypertensive agent, N-(2,5-dimethyl-1H-pyrrol-1-yl)-6-(4-morpholinyl)-3-pyridazinamine hydrochloride. II: Studies in the dog

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