2-(Difluoromethyl)-DL-ornithine

Definition

ChEBI: Eflornithine is a fluoroamino acid that is ornithine substituted by a difluoromethyl group at position 2. It has a role as a trypanocidal drug. It is a fluoroamino acid and an alpha-amino acid. It is functionally related to an ornithine.

Antimicrobial activity

Cultured bloodstream trypomastigotes of T. brucei are relatively insensitive, but high doses are effective against bloodstream and CNS infections of T. brucei brucei and T. brucei gambiense in rodents, provided a strong antibody response is also present. Eflornithine entry into the CNS can be enhanced with suramin. T. brucei rhodesiense infections do not respond. Synergy with some arsenicals has been demonstrated.
Eflornithine is active against P. falciparum in experimental models and against Leishmania promastigotes and Giardia lamblia in culture.

Acquired resistance

Acquired resistance in T. brucei gambiense in West Africa has not been reported. East African T. brucei rhodesiense strains are innately less sensitive. Reported treatment failures are thought to be associated with severity of disease.

Pharmaceutical Applications

An analog of ornithine, formulated as the hydrochloride for intravenous infusion. It is freely soluble in water.

Pharmacokinetics

Oral absorption: 55%
C_max 10 mg/kg oral: c. 7 mg/L after 4 h
200 mg/kg intravenously: 15.9 mg/L (87.5 nmol/mL) (mean)
Plasma half-life: 3.3 h
Volume of distribution: 0.34 L/kg
Plasma protein binding: Very low
Renal clearance is 83%, with most eliminated unchanged. In a study in Zaire the mean serum concentration in children under 12 years old was half that of adults, probably due to more rapid renal clearance. CNS penetration is good in adult patients, with a CSF:plasma ratio of 0.91 at the end of administration for 14 days. However, the CSF:plasma ratio in children under 12 years old was 0.58. Relapses have been recorded in patients in whom CSF levels dropped below 9 mg/L (50 nmol/mL) at the end of treatment.

Clinical Use

2-(Difluoromethyl)-DL-ornithine has been used speculatively for treatment of Pn. jirovecii infections in AIDS patients. Co-administration with oral nifurtimox has been added to the World Health Organization (WHO) List of Essential Medicines for second-stage sleeping sickness caused by T. brucei gambiense.

Side Effects

Osmotic diarrhea and bone marrow suppression are common, and up to 50% of sleeping sickness patients develop leukopenia. Reversible anemia and thrombocytopenia have been observed. Convulsions and seizures, different from those observed in melarsoprol-induced encephalopathy, have been reported in 4–18% of treated sleeping sickness patients but not in patients treated for Pn. jirovecii pneumonia. This difference might be due to the CNS inflammation associated with sleeping sickness.