Disposition of venlafaxine enantiomers in rats with hepatic encephalopathy after chronic drug treatment.
Portacaval shunted (PCS) rats, a model of hepatic encephalopathy, and control animals were administered racemic venlafaxine for 14 days (10 mg/kg). The levels of the S- and R-enantiomers and the S/R-enantiomer ratios of venlafaxine and its metabolites were assessed by an enantiomer-selective chromatographic assay in serum, brain parenchyma, and brain dialysate of both groups. Higher levels of the S- and R-enantiomers of venlafaxine were found in serum and brain of PCS vs. normal rats (median values of S- and R-venlafaxine in serum: 290 and 201 nM in PCS; 97 and 66 nM in normal rats; median values of S- and R-venlafaxine in cortex: 956 and 939 nM in PCS; 357 and 318 nM in normal rats). Interestingly, similar S/R-venlafaxine ratios were observed in PCS and normal rats both in serum (S/R = 1.4) and brain compartments (S/R = l.0-1.1). These findings may have clinical relevance for the safety of venlafaxine in chronic hepatic encephalopathy.
Wikell
Cecilia
C
Department of Clinical Pharmacology, Lund University, Lund, Sweden. Cecilia.Wikell@klinfarm.lu.se
Eap
Chin B
CB
Josefsson
Martin
M
Apelqvist
Gustav
G
Ahlner
Johan
J
Baumann
Pierre
P
Bengtsson
Finn
F
D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics*; D001921:Brain / Q000378:metabolism; D003511:Cyclohexanols / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics*; D004195:Disease Models, Animal; D006501:Hepatic Encephalopathy / Q000188:drug therapy* / Q000378:metabolism*; D006801:Humans; D008297:Male; D011167:Portacaval Shunt, Surgical; D051381:Rats; D017207:Rats, Sprague-Dawley; D012449:Safety; D013237:Stereoisomerism; D000069470:Venlafaxine Hydrochloride
D018687:Antidepressive Agents, Second-Generation; D003511:Cyclohexanols; D000069470:Venlafaxine Hydrochloride