Pharmacokinetics of Corticoids

PHARMACOKINETICS

All natural and synthetic corticoids, except DOCA are absorbed and are effective by the oral route. Water soluble esters, e.g. hydrocortisone hemisuccinate, dexamethasone sod. phosphate can be given i.v. or i.m., act rapidly and achieve high concentrations in tissue fluids. Insoluble esters, e.g. hydrocortisone acetate, triamcinolone acetonide cannot be injected i.v., but are slowly absorbed from i.m. site and produce more prolonged effects.

Hydrocortisone undergoes high first pass metabolism, has low oral: parenteral activity ratio. Oral bioavailability of synthetic corticoids is high.

Hydrocortisone is 90% bound to plasma protein, mostly to a specific cortisolbinding globulin (CBG; transcortin) as well as to albumin. Transcortin concentration is increased during pregnancy and by oral contraceptives—corticoid levels in blood are increased but hypercorticism does not occur, because free cortisol levels are normal.

The corticosteroids are metabolized primarily by hepatic microsomal enzymes. Pathways are—

·        Reduction of 4, 5 double bond and hydroxylation of 3keto group.

·        Reduction of 20keto to 20hydroxy form.

·  Oxidative cleavage of 20C side chain (only in case of compounds having a 17hydroxyl group) to yield 17ketosteroids.

These metabolites are further conjugated with glucuronic acid or sulfate and are excreted in urine.

The plasma t½ of hydrocortisone is 1.5 hours. However, the biological t½ is longer because of action through intracellular receptors and regulation of protein synthesis—effects that persist long after the steroid is removed from plasma.

The synthetic derivatives are more resistant to metabolism and are longer acting.

Phenobarbitone and phenytoin induce metabolism of hydrocortisone, prednisolone and dexamethasone, etc. to decrease their therapeutic effect.