Effect of citalopram on brain serotonin release in experimental hepatic encephalopathy: implications for thymoleptic drug safety in liver insufficiency.
In the present study, effects of citalopram (CIT) on brain 5-hydroxytryptamine (5-HT) release in experimental chronic hepatic encephalopathy (HE) were investigated. Neocortical administration of CIT (1.0 microM) increased the brain 5-HT output to a similar extent in portacaval shunted (PCS) rats and sham-operated controls, indicating that a previous described mismatch between increased 5-HT turnover and unchanged release in PCS rats is not explained by an accelerated brain 5-HT reuptake. Subsequent systemic administration of CIT (5 mg/kg subcutaneously) resulted in a more pronounced attenuation of the brain 5-HT release in PCS rats than in sham-operated controls, possibly indicating a higher susceptibility to indirect mid-brain 5-HT1A autoreceptor activation in experimental portal-systemic encephalopathy (PSE). A KCl (60 mM) challenge in the presence of locally administered CIT (1 microM) induced a more marked neocortical 5-HT response in PCS rats than in sham-operated controls, confirming previous results of a higher than normal amount of 5-HT available for depolarization-induced release in PCS rats. Although the pharmacodynamic parameters in this study was investigated for CIT, the likelihood of a parallel pharmacokinetic alteration existing for this drug in the PCS condition also was indicated. It is thus suggested that otherwise generally safe central nervous system 5-HT-active drugs may represent a potential hazard in patients with liver failure with or without PSE.
Bergqvist
P B
PB
Department of Clinical Pharmacology, Lund University, Sweden.
Wikell
C
C
Hjorth
S
S
Apelqvist
G
G
Bengtsson
F
F
D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001711:Biotransformation; D001923:Brain Chemistry / Q000187:drug effects*; D015283:Citalopram / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D006501:Hepatic Encephalopathy / Q000378:metabolism*; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D007267:Injections; D007279:Injections, Subcutaneous; D008297:Male; D017551:Microdialysis; D019579:Neocortex / Q000187:drug effects / Q000378:metabolism; D011189:Potassium Chloride / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism*; D017367:Selective Serotonin Reuptake Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*
D000928:Antidepressive Agents; D015283:Citalopram; D006897:Hydroxyindoleacetic Acid; D011189:Potassium Chloride; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors