A feature common to all selective serotonin reuptake inhibitors (SSRIs) is that they are believed to act as antidepressant drugs because of their ability to reversibly block the reuptake of serotonin (5-hydroxytryptamine; 5-HT) in the synaptic cleft. From a chemical perspective, however, they show distinct differences. Consequently, the pharmacokinetic behaviour of of the drugs can be very different, and these pharmacokinetic differences may have a major influence on their clinical profiles of action. All SSRIs have a great affinity for the 5-HT reuptake carrier in the synaptic cleft in the central nervous system, with much less affinity for the noradrenaline (norepinephrine) reuptake carrier, and for alpha- and beta-adrenergic, dopamine, histamine, 5-HT and muscarine receptors. Fluoxetine and citalopram are available as racemic mixtures, the isomers of fluoxetine having almost equal affinity to the 5-HT reuptake carrier, while the reuptake inhibitor properties of citalopram reside almost exclusively in the (+)-isomer. Norfluoxetine, one of the metabolites of fluoxetine, has a selectivity for the 5-HT reuptake carrier comparable with that of fluoxetine. Gastrointestinal absorption of the SSRIs is generally good, with peak plasma concentrations observed after approximately 4 to 6h. Absolute bioavailability of citalopram is almost 100%, whereas it is likely that the other compounds undergo (substantial) first-pass metabolism. Apparent oral clearance values after single doses range from 26 L/h (citalopram) to 167 L/h (paroxetine), while after multiple doses oral clearance is markedly reduced, particularly for fluoxetine and paroxetine. Plasma protein binding of fluoxetine, paroxetine and sertraline is > or = 95%; values for fluvoxamine (77%) and citalopram (50%) are much lower. For all compounds, however, protein binding interactions do not seem to be of great importance. Although many attempts were made, to date no convincing evidence exists of a relationship between plasma concentrations of any of the SSRIs and clinical efficacy. Elimination occurs via metabolism, probably in the liver. Renal excretion of the parent compounds is of minor importance. Metabolites of fluvoxamine and fluoxetine are predominantly excreted in urine; larger quantities of metabolites of paroxetine (36%) and sertraline (44%) are excreted in faeces. The half-lives of fluvoxamine, paroxetine, sertraline and citalopram are approximately 1 day. The half-life of fluoxetine is approximately 2 days (6 days after multiple doses), and that of the active metabolite norfluoxetine is 7 to 15 days. The metabolism of paroxetine, and possibly also of fluoxetine, is under genetic control of the sparteine/debrisoquine type. Available data indicate that metabolism of SSRIs is impaired with reduced liver function.(ABSTRACT TRUNCATED AT 400 WORDS)
The pharmacokinetics and hemodynamic effects of nifedipine were studied in patients with liver cirrhosis and in age-matched healthy control subjects. In a randomized order each subject received nifedipine by intravenous infusion (4.5 mg in 45 minutes) and as a tablet (20 mg). After intravenous nifedipine patients had a longer elimination t1/2 (420 +/- 254 vs. 111 +/- 22 minutes; P less than 0.01), a greater volume of distribution (1.29 +/- 0.60 vs. 0.97 +/- 0.42 L/kg), and a lower systemic clearance (233 +/- 109 vs. 588 +/- 140 ml/min; P less than 0.001). Plasma protein binding of nifedipine was lower in the patients (P less than 0.001). After oral nifedipine systemic availability was much higher in patients (90.5% +/- 26.2% vs. 51.1% +/- 17.1%; P less than 0.01) and maximal in patients with a portacaval shunt. Blood pressure decreased and heart rate increased after intravenous nifedipine and these effects could be fitted to plasma concentrations by a sigmoidal model. Maximal effects on heart rate and diastolic blood pressure were not different in liver cirrhosis. When free drug levels were considered, the concentrations corresponding to half the maximal effect were also not different. Blood pressure changes with oral nifedipine were comparable with those after intravenous infusion. We conclude that in patients with liver cirrhosis the pharmacokinetics of nifedipine are considerably altered; dose reduction is recommended when such patients need oral nifedipine.
Objective: To assess whether fluvoxamine alters the pharmacokinetics of alcohol or potentiates alcohol‐related impairment of cognitive function. Methods: The study design required partially “blinded” balanced crossover studies, each involving 12 healthy male volunteers who each received a 40 gm dose of intravenous or oral alcohol after single and multiple doses of 50 mg fluvoxamine. Main outcome measures for pharmacokinetics were venous blood alcohol and plasma fluvoxamine. Main outcome measures for pharmacodynamics were word recall, simple and choice reaction time, number vigilance, memory scanning, and word recognition. Results: The pharmacokinetics of intravenous alcohol were not affected by concomitant administration of fluvoxamine. Compared with placebo‐alcohol, alcohol slightly increased the rate of fluvoxamine absorption, but the area under the plasma concentration‐time curve from 0 to 12 hours at steady state was unchanged. As expected, alcohol significantly impaired cognitive function in volunteers. However, fluvoxamine did not potentiate the effects of alcohol and in some instances appeared to reverse the effects or reduce their duration. Fluvoxamine was well tolerated: only mild adverse effects were reported, and none of those required intervention. Conclusion: Fluvoxamine does not interact significantly with alcohol or potentiate alcohol‐related impairment of cognitive function. Clinical Pharmacology and Therapeutics (1992) 52, 427–435; doi:
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