Chemical formula: C₂₄H₄₀O₄ Molecular mass: 392.572 g/mol PubChem compound: 222528
Deoxycholic acid is a cytolytic drug, which when injected into localized subcutaneous fat, physically disrupts the cell membrane of adipocytes. The destruction of adipocytes elicits a tissue response in which macrophages are attracted to the area to eliminate cellular debris and lipids, which are then cleared through natural processes. This is followed by the appearance of fibroblasts and observed thickening of fibrous septa suggesting an increase in total collagen (i.e. neocollagenesis).
Endogenous deoxycholic acid plasma levels are highly variable within and between individuals; most of this natural secondary bile acid is sequestered in the enterohepatic circulation system. Pharmacokinetics of exogenous deoxycholic acid administered via treatment with deoxycholic acid was compared against this endogenous background.
Deoxycholic acid from deoxycholic acid is rapidly absorbed following subcutaneous injection. After dosing with the maximum recommended single treatment with deoxycholic acid (100 mg), maximum plasma concentrations (mean Cmax) were observed with a median tmax of 6 minutes after injection. The mean Cmax value was 1036 ng/ml and was 2.3-fold higher than average Cmax values observed during a 24-hour baseline endogenous period in the absence of deoxycholic acid. At the maximum recommended single treatment dose (100 mg), deoxycholic acid exposure (AUC0-24) was less than 2-fold higher over endogenous exposure.
Plasma AUC0-24 increased in a dose-proportional manner up to 100 mg. Post-treatment deoxycholic acid plasma levels returned to the endogenous range within 24 hours. No accumulation is expected with the proposed treatment frequency.
The volume of distribution was estimated to be 193 L and is independent of the dose up to 100 mg. Deoxycholic acid is extensively bound to proteins in plasma (98%).
Endogenous deoxycholic acid is a product of cholesterol metabolism and is excreted intact in feces. Deoxycholic acid from deoxycholic acid joins the endogenous bile acid pool and is excreted along with the endogenous deoxycholic acid. Deoxycholic acid is eliminated via hepatic transport proteins from the blood to the bile without any significant contribution of metabolism. Deoxycholic acid is not an in vitro inhibitor of the enzymes CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6 and 3A4. Deoxycholic acid did not induce CYP1A, 2B6 and 3A at a clinically level.
Deoxycholic acid is not an in vitro inhibitor of the transporters BSEP, MRP2, MRP4, MDR1, BCRP, OATP1B1, OATP1B3, OAT1, OAT3, OCT1, OCT2, OATP2B1 and ASBT. Deoxycholic acid inhibited NTCP with an IC50 of 2.14 µM in vitro.
Deoxycholic acid has not been studied in patients with renal impairment. Bile acids including deoxycholic acid are excreted in the urine in negligible amounts; renal impairment is unlikely to influence deoxycholic acid pharmacokinetics.
Deoxycholic acid has not been studied in patients with hepatic impairment. Considering the intermittent dose frequency, the small dose administered that represents approximately 3% of the total bile acid pool, and the highly variable endogenous deoxycholic acid levels, the pharmacokinetics of deoxycholic acid following deoxycholic acid injection is unlikely to be influenced by hepatic impairment.
No dose adjustment is considered necessary. Caution should be exercised in elderly patients.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, toxicity to reproduction and development.
In repeat dose toxicity studies of up to 6 months in rats and 9 months duration in dogs, there was no indication of local or systemic pre-neoplastic responses to subcutaneous deoxycholic acid administration. In these studies, the maximum intended clinical dose was exceeded by 2.5 to 12.5-fold (based on mg/injection site) and 2 to 3-fold (based on quantified systemic exposure) in rats and dogs, respectively. Further, in contrast to the maximum intended clinical regimen of monthly injections for up to 6 sessions, deoxycholic acid injections were administered twice monthly for up to 13 total doses in rats and 20 total doses in dogs. No carcinogenicity studies have been conducted with deoxycholic acid.
Deoxycholic acid was negative in a standard battery of in vitro (microbial reverse mutation assay and chromosomal aberration assay) and in vivo (micronucleus assay) genetic toxicology assays.
Inconclusive findings of missing intermediate lung lobe were noted in rabbits in the embryo-fetal toxicity study. The finding was significantly increased in the 30mg/kg group but was evident also at the lowest concentration 10mg/kg. This dose was associated with maternal local toxicity. The clinical significance of the finding is unclear.
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