Phenobarbital-Induced Alterations in Vitamin D Metabolism

Abstract

A B S T R A C T The metabolic fate of intravenously injected vitamin D3-1,2-'H (Ds-'H) was studied in two normal individuals on chronic phenobarbital therapy. Silicic acid column chromatography of lipid-soluble plasma extracts obtained serially for 96 hr after D3-'H injection demonstrated a decreased plasma Ds-'H halflife and increased conversion to more polar metabolites. The polar metabolites formed included several with chromatographic mobility similar to known biologically inactive vitamin D metabolites and one with chromatographic mobility identical to 25-hydroxycholecalciferol. Disappearance of this latter material was also accelerated. A child with rickets and a normal volunteer studied before and after a 2 wk course of phenobarbital therapy demonstrated similar alterations in D3-'H metabolism. When liver microsomes from 3-wk-old Sprague-Dawley rats treated with phenobarbital were incubated with D3-'H, polar metabolites were produced with chromatographic mobility similar to the plasma D3-'H metabolites from phenobarbital-treated humans. Similar incubations employing 25-hydroxycholecalciferol-26,27-2H as the substrate also demonstrated an increased conversion to polar metabolites. The data suggest that the reported increased incidence of osteomalacia observed in patients on chronic anticonvulsant therapy may be the result of an accelerated conversion of vitamin D and its active metabolite, 25-hydroxycholecalciferol, to polar metabolites by druginduced liver microsomal enzymes.

Effects of Chronic Administration of Zonisamide, an Antiepileptic Drug, on Bone Mineral Density and Their Prevention With Alfacalcidol in Growing Rats

“…A lack of vitamin D is well known to lead to rickets and / or osteomalacia in animals (11). Antiepileptic agents induced liver microsomal P-450-containing oxidases, which subsequently leads to an increased rate of catabolism of vitamin D and its derivatives to inactive metabolites (12,13). However, the present biochemical data indicated that the serum 25OHD levels are not decreased compared with that of the normal group.…”

Bone density and bone turnover markers in patients with epilepsy on chronic antiepileptic drug therapy

“…This drug is known to impair bone metabolism through several mechanisms. First, it stimulates hepatic mixed function oxidase activity, accelerating the breakdown of vitamin D metabolites (11). In addition, both phenobarbital and phenytoin interfere with active transport of calcium in the small intestine (21).…”

“…Classical AEDs associated with abnormal bone and mineral metabolism are those that induce cytochrome P450 enzymes, such as carbamazepine, phenytoin and phenobarbital (9,10). These drugs induce hepatic microsomal enzymes that increase catabolism of 25OHD (11). Other drugs that are not enzyme inducers, such as sodium valproate, may exert indirect effects on bone metabolism by altering renal function (12).…”

Vitamin D-dependency Rickets in Institutionalized, Mentally Retarded Children on Long Term Anticonvulsant Therapy. II. The Response to 25-Hydroxycholecalciferol and to Vitamin D2

“…Chronic phenobarbital ingestion has been shown to increase the rate of disappearance of 3 H-vitamin D 3 from plasma in humans (15)(16)(17). Liver microsomes from phenobarbital-treated animals are capable of increasing hydroxylation of steroid hormones (7,20,24) and of converting 3 H-labeled vitamin D 3 and 3 H-labeled 25-OH-D 3 rapidly to more polar metabolites in vitro [15].…”