Pharmacokinetics of the S(+) and R(-) enantiomers of vigabatrin during chronic dosing in a patient with renal failure.
OBJECTIVE
To study the pharmacokinetics of vigabatrin in a patient affected with tuberous sclerosis who developed major agitation and aggression, while receiving vigabatrin orally (1.5 g every 12 h) and in whom impaired renal function was diagnosed.


METHODS
The patient received vigabatrin (0.5 g day(-1)). A pharmacokinetic study of the S(+) and R(-) enantiomers of vigabatrin was performed before and during dialysis. Plasma concentrations were measured at 0, 1, 2, 3, 4, 6, 12, 18 and 24 h by a specific GCMS assay.


RESULTS
Before dialysis, the maximum and minimun plasma concentrations of vigabatrin at steady-state were lower for the S(+) than for the R(-) enantiomer, while the apparent oral clearance was higher for the S(+) than for the R(-) enantiomer (2.97 vs 0.48 l h(-1)). In addition, the haemodialysis clearance was similar for the two enantiomers (4.96 vs 5.15 l h(-1)).


CONCLUSIONS
Vigabatrin is an irreversible inhibitor of GABA-transaminase, effective in the treatment of drug-resistant epilepsy and reported to be eliminated unchanged by renal excretion. Although vigabatrin is known to have stereoselective kinetics, the difference in plasma dry concentrations and pharmacokinetics of the S(+) and R(-) enantiomers that we observed during long term administration at high doses in a patient with impaired renal function, has not been reported before. The question remains of the potential toxicity of the high levels of the R(-) enantiomer.
Jacqz-Aigrain
E
E
Department of Pediatric Clinical Pharmacology, Hôpital Robert Debre, Paris, France.
Guillonneau
M
M
Rey
E
E
Macher
M A
MA
Montes
C
C
Chiron
C
C
Loirat
C
C
D000328:Adult; D000927:Anticonvulsants / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D006801:Humans; D007676:Kidney Failure, Chronic / Q000150:complications / Q000378:metabolism* / Q000628:therapy; D017582:Renal Replacement Therapy; D013237:Stereoisomerism; D014402:Tuberous Sclerosis / Q000150:complications / Q000188:drug therapy*; D020888:Vigabatrin; D005680:gamma-Aminobutyric Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics
D000927:Anticonvulsants; D004791:Enzyme Inhibitors; D005680:gamma-Aminobutyric Acid; D020888:Vigabatrin