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Prednisolone Also Binds to Transcortin • Other Synthetic GS Only Bind to Albumin

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Prednisolone Also Binds to Transcortin • Other Synthetic GS Only Bind to Albumin PK/PD considerations for corticosteroids P L Toutain, National Veterinary School, Toulouse, France Wuhan October 2015 1 Anti-inflammatory drugs Corticosteroids NSAIDs 2 Glucocorticoids: main properties • Glucocorticosteroids (GCS) are broad and potent anti- inflammatory drugs. • They are extensively used to mitigate or suppress inflammation associated with a variety of conditions especially joint and respiratory system inflammation. • GCs are not curative: • GCs are only palliative symptomatic treatments and chronic use of GCs can be, in fine , detrimental • GCs possess many other pharmacological properties (not reviewed in this presentation) 3 The cortisol or hydrocortisone 4 Cortisol : An endogenous hormone and a surrogate endpoint of the duration of the GCS effects; it physiology should be understood to use properly GCS 5 Cortisol synthesis • All GCs used in therapeutics are synthetic derivatives of cortisol. • Cortisol (hydrocortisone) is synthesized in the adrenal cortex and it is the main corticosteroid hormone in most species. 6 Steroids synthesis by the adrenal gland Aldosterone Cortisol Androgens Epinephrine (adrenalin) 7 Cortisol ou Hydrocortisone structure – activity relationship Three structural properties are required for a GC activity (i.e. for cortisol to bind to GC receptor) 8 Cortisol (hydrocortisone) • Minimal information on cortisol physiology (secretion, distribution & elimination ) needs to be known to understand the clinical pharmacology of GCS 9 Plasma cortisol • Cortisol levels are very different in domestic species • Pattern of secretion – Circadian rhythm (h) – Pulsatilty (minute) 10 Plasma cortisol level Plasma concentration (ng/mL) 600 500 400 300 Series1 200 100 0 1 2 3 4 5 11 Plasma cortisol levels: circadian rhythm & pulsatility Toutain et al. Domestic.Anim.Endocrinol. 1988, 5:55 12 All dogs Rest dogs 13 Plasma cortisol levels: circadian rhythm & pulsatility • The cortisol secretion is pulsatile with minute- to-minute variations in the plasma cortisol concentrations making the interpretation of snapshot plasma samples difficult. 14 Modeling of circadian cortisol 15 Binding of cortisol to plasma proteins • In mammalian plasma, cortisol binds to a specific alpha-glycoprotein: corticosteroid-binding globulin (CBG). • Binding to CBG is saturable (Bmax) B max Free Total Free NS Free Kd Free 16 Binding of synthetic GCS to plasma protein • Prednisolone also binds to transcortin • Other synthetic GS only bind to albumin Prednisolone cannot be used for an adrenal suppression test 18 Adrenal suppression test Prednisolone vs. Dexamethasone (IV) Prednisolone (600µg/kg) Dexamethasone Immediate decrease of cortisol due (50µg/kg) to the displacement of cortisol Delayed decrease due to the from the CBG by prednidsolone suppression of ACTH secretion Cortisol concentration (ng / ml) Cortisol concentration (ng / ml) 100 80 80 60 60 40 40 20 20 0 0 0.25 0.5 1 2 4 8 12 24 48 0 0 0.16 0.5 1 2 3 4 6 24 48 72 96 Hours Hours 19 Toutain et al., Am.J.Vet.Res 1985, 9: 1750 Urine cortisol • The advantage of urine cortisol is due to the fact, that unlike plasma sample, a snapshot urine sample is representative of the total cortisol secretion over the entire preceding period of time separating two micturitions, i.e. it is not subjected to time-to-time variation like plasma cortisol. 20 Urine cortisol • Diagnostic of Cushing syndrom ) 6 3000 - 1000 300 100 30 10 3 Rapport : Rapport 1 0.3 healthy dogs with dogs with cortisol/créatinine (x10 cortisol/créatinine dog hyperadrenocorticism polyuria/polydipsia Urine Cortisol : cushing : 118 ± 15 ng/mL; Sensitivity of the test 100%. Spécificity= 22% (confusion with dogs having a poluuric/polydipsic syndrom Cortic 00.21 Feldman, JAVMA 1992, 200 : 1637 Urine cortisol (doping control) • International threshold: 1µg/ml or 1000ng/mL 22 Urine cortisol Population investigations (n=254) Average 48ng/mL (geometric) maximum 388 Probability Urine exceeding concentration ng/ml 10-3 611 10-4 1025 10-5 1606 Popot & al EVJ 1997 29 220-229 23 Regulation of cortisol secretion to be understood to predict the suppressive effect of GCS 24 Suppressive effect of corticosteroids on the hypothalamic pituitary adrenal axis (HPA) SNC ACTH CRF • Stimulation of cortisol synthesis (no storage) ACTH • Trophic action on the ACTH zona fasciculata and reticularis CORTISOL Cortic 00A.26 Suppressive effect of synthetic GC Control Short term Long term SNC SNC SNC CRF CRF CRF - - ACTH ACTH CS ACTH ACTH ACTH ACTH COR COR t t Cortic 00A.27 Cortisol bind to specific receptor Inactive glucocorticoid receptors (GR) are located in the cytoplam; after binding to cortisol, the GR is activated and translocated into nucleus; then, GR bind the glucocorticoid response element (GRE) in the DNA and regulate the responsive gene (activation). The GR can also inhibit transcription by a direct protein/protein interaction 28 Corticosteroid Mechanism of action Lipocortin Corticoids + Plasma membrane Inhibition of phospholipase A2 PLA2 (PLA2) NSAIDs Arachidonic acid cyclooxygenases lipoxygenase PG, TXA2 Leucotrienes Ferguson In: Adams, 1995 Cortic 00A.29 Métabolisme du cortisol CH2 O H 20 et 20ß dihydrocortisone 20ß dihydrocortisol HOCH CH3 ...... OH HO 11 ß - CH3 deshydrogénase CH2 O H CH2 O H Cortisone CORTISOL C = O C = O O CH3 ...... OH CH3 ...... OH HO O CH3 CH3 O O 6ß hydroxycortisol CH2 O H 11-Ketoetiocholanolone 11ß - hydroxy C = O O etiocholanolone O CH CH3 ...... OH 3 CH3 HO O HO CH CH3 3 CH3 HO HO O H H OH 32 Cortisol metabolism is used as a biomarker of drug metabolism (polymorphism associated to CYP3A) 33 Corticosterioids - Filiation - 34 Synthetic glucocorticosteroids (GCs) • Chemical modification of cortisol have generated derivatives with: – Greater separation of glucocorticoid and mineralocorticoid activity(selectivity) – Higher potency – Longer duration of action • Chemical modification of cortisol do not have generated derivatives with: – Separation of AI effect from effect on carbohydrates, lipids and proteins metabolism or without adrenal suppression 35 The main CS used in veterinary medicine for systemic administration • Prednisolone • Méthylprednisolone • Dexaméthasone • Triamcinolone acétonide • Fluméthasone • Isoflupredone Cortic 00A.36 The main CS used for systemic inhalation Fluticasone propionate Beclométhasone 17 monopropinate Budesonide Cortic 00A.37 The two main group of CS Cortisol Non halogenated - Halogeneted- derivatives derivatives No mineralocorticoid activity Prednisolone With mineralocorticoid Dexmethasone, Methylprednisolone activity betamethasone budenoside Isoflupredone triamcinolone acetonide betamethasone 38 Synthetic derivatives of cortisol • All therapeutic GCs have a 21-carbon cortisol skeleton • A variety of GCs have been developed to increase the potency of the anti- inflammatory effect and to decrease or even suppress the mineralocorticoid effects of cortisol 39 Cortisone Δ Prednisone GC filiation C6 CH3 C11 C11 OOH OOH Methylprednisone C11 OOH Methylprednisolone C6 C16 & C17 Triamcinolone acetonide CH3 OH - TRIAMCINOLONE C16 Cortisol Δ Prednisolone C9 F Fluoro- CH3 - Dexamethasone prednisolone - Betamethasone (Predef 2X) C6 C16 PROPERTY C9 CH3 - Flumethasone ANTI-INFLAMMATORY - GLUCOCORTICOID MINERALOCORTICOID 40 The 2 main PD parameters: Emax ED50/EC50 Emax 1 1 1 2 Emax 2 2 EC501 EC502 Efficacy Potency Issue for analysts Issue for vets Potent drug=low LOQ ECVPT Toulouse 2009 - 44 Relative potency of corticosteroids glucocorticoïd Minéralocorticoïd Substances Duration action action action Cortisol 1 1 12h Prednisolone 5 0.8 24h Méthylprednisolone 5 0.8 24h Isoflupredone 25 25 48-72h Triamcinolone 5 0 24h Triamcinolone acétonide 30 0 48-72h Dexamethasone 25 0 48-72h betamethasone 25 0 48-72h Flumethasone 120 0 48-72h Order of potency of the different corticoids is now internationally accepted and cannot be reconsidered even if there are some discrepancies in the literature 47 Relative anti-inflammatory (AI) potency of topical GC used for inhalation (1=dexamethasone) Substances AI Potency Comments (1=dexamethasone) Beclomethasone 0.5 A prodrug of dipropionate beclomathasone monopropionate Beclomethasone 17- 13 Active moiety of monopropionate beclomethasone dipropionate Beclomethasone 0.5 Metabolite of beclomethasone monopropionate Fluticasone propionate 18 Active substance Budesonide 9 Triamcinolone acetonide 50 48 Corticoïds : esters & Formulations 49 Corticoïdes : Substance active vs. esters Substances (principes actifs) Esters alcohol (prodrogues) Non Hydrosolubles hydrosolubles 50 Most GCs are administered as esters substance Hydrosoluble Non hydrosoluble (IV) (depot) Phosphate Acetate Succinate Butyrate ………. ……… 52 Most GCs are administered as esters • Most GC are administered as esters, • Esterification considerably alters the disposition and duration of the GC action. – Esterification with a monoacid (like acetic acid) at C- 21 gives non-hydrosoluble drugs that can be used as long-acting formulations when administered by the intramuscular, subcutaneous or IA routes. – Esterification of the same parental drug by a diacid (such as succinic acid) can give a hydrosoluble ester enabling a salt to be formed (e.g. a sodium succinate). Phosphate esters are also hydrosoluble. 53 Formulations of corticoïds Méthylprednisolone (medrol) CH2 OH C = O CH ...... OH HO 3 CH3 Methylprednisolone Methylprednisolone sodium succinate acetate O C22H30O5= 374,5 (Solumedrol®) CH3 (Dépomedrol®) CH2 O - CO - CH3 CH2 - O - CO - (CH2)2 - COONa C = O C = O CH3 ...... OH CH ...... OH HO HO 3 CH 3 H CH3
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