Citalopram (CITA) is available as a racemic mixture and as a pure enantiomer. Its antidepressive action is related to the (+)-(S)-CITA and to the metabolite (+)-(S)-demethylcitalopram (DCITA). In the present investigation, a method for the analysis of CITA and DCITA enantiomers in human and rat plasma was developed and applied to the study of pharmacokinetics. Plasma samples (1 ml) were extracted at pH 9.0 with toluene:isoamyl alcohol (9:1, v/v). The CITA and DCITA enantiomers were analyzed by LC-MS/MS on a Chiralcel OD-R column. Recovery was higher than 70% for both enantiomers. The quantification limit was 0.1 ng/ml, and linearity was observed up to 500 ng/ml plasma for each CITA and DCITA enantiomer. The method was applied to the study of the kinetic disposition of CITA administered in a single oral dose of 20 mg to a healthy volunteer and in a single dose of 20 mg/kg (by gavage) to Wistar rats (n = 6 for each time). The results showed a higher proportion of the (-)-(R)-CITA in human and rat plasma, with S/R AUC ratios for CITA of 0.28 and 0.44, respectively. S/R AUC ratios of DCITA were 0.48 for rats and 1.04 for the healthy volunteer.

The present data permit us to infer that type-2 diabetes mellitus alters the kinetic disposition of the (+)-N eutomer and (-)-N distomer, presumably due to a lower activity of CYP3A4, although it does not modify the clinical effect brought about by the reduction in BP.

Background: Critically ill patients show a high, albeit variable, prevalence of augmented renal clearance (ARC). This condition has relevant consequences on the elimination of hydrophilic drugs. Knowledge of risk factors for ARC helps in the early identification of ARC. The aims of this study were evaluation of (1) risk factors for ARC and (2) the prevalence of ARC in critically ill patients over a period of 1 year. Methods: A retrospective cohort study was performed for all consecutive patients admitted to our intensive care unit (ICU). Augmented renal clearance was defined by a creatinine clearance ≥130 mL/min/1.73 m2. “Patient with ARC” was defined as a patient with a median of creatinine clearance ≥130 mL/min/1.73 m2 over the period of admission. Four variables were tested, Simplified Acute Physiology Score II (SAPS II), male gender, age, and trauma as cause for ICU admission. An analysis (patient based and clearance based) was performed with logistic regression. Results: Of 475 patients, 446 were included in this study, contributing to 454 ICU admissions and 5586 8-hour creatinine clearance (8h-CLCR). Overall, the prevalence of patients with ARC was 24.9% (n = 113). In a subset of patients with normal serum creatinine levels, the prevalence was 43.0% (n = 104). Of the set of all 8h-CLCR measurements, 25.4% (1418) showed ARC. In the patient-based analysis, the adjusted odds ratio was: 2.0 (confidence interval [CI]:1.1-3.7; P < .05), 0.93 (CI: 0.91-0.94; P < .01), 2.7 (CI: 1.4-5.3; P < .01), and 0.98 (CI: 0.96 -1.01; P = .15), respectively, for trauma, age, male sex, and SAPS II. In the clearance-based analysis, the adjusted odds ratio were 1.7 (CI: 1.4-1.9; P < .01), 0.94 (CI: 0.932-0.942; P < .01), and 2.9 (CI: 2.4-3.4; P < .01), respectively, for trauma, age, and male sex. Conclusions: Trauma, young age, and male sex were independent risk factors for ARC. This condition occurs in a considerable proportion of critical care patients, which was particularly prevalent in patients without evidence of renal dysfunction.

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Aims The aim of the present study was to investigate the impact of human visceral leishmaniasis (VL) and curative chemotherapy on the activity of cytochrome P450 (CYP) 3A, CYP2C9 and CYP2C19 in patients from an endemic region in Brazil. Methods Adult patients with parasitologically confirmed VL were given a CYP phenotyping cocktail, comprising midazolam, omeprazole and losartan, immediately before (Study phase 1), 2–3 days (phase 2) and 3–6 months (phase 3) after curative VL chemotherapy. CYP activity was assessed by the apparent clearance of midazolam (CYP3A), omeprazole/5‐hydroxyomeprazol ratio in plasma (CYP2C19) and losartan/E3174 ratio in urine (CYP2C9). Results Mean values (95% confidence interval) in phases 1, 2 and 3 were, respectively: log apparent midazolam clearance, 1.21 (1.10–1.31), 1.45 (1.32–1.57) and 1.35 (1.26–1.44) ml min–1 kg–1; omeprazole/5‐hydroxyomeprazole ratio, 0.78 (0.61–0.94), 0.45 (0.27–0.63) and 0.37 (0.20‐0.55); losartan/E3174 ratio, 0.66 (0.39–0.92), 0.35 (0.20–0.50) and 0.35 (0.16–0.53). Analysis of variance revealed significant differences in CYP3A (P = 0.018) and CYP2C19 (P = 0.008), but not CYP2C9 (P = 0.11) phenotypic activity, across the three study phases. Conclusion The phenotypic activities of CYP3A4 and CYP2C19 were significantly reduced during acute VL compared with post‐chemotherapy. We propose that increased plasma concentrations of proinflammatory cytokines during active disease account for the suppression of CYP activity. The failure to detect significant changes in CYP2C9 activity in the overall cohort may reflect differential effects of the inflammatory process on the expression of CYP isoforms, although the possibility of insufficient statistical power cannot be dismissed.

Albendazole is considered the drug of choice for neurocysticercosis. It is frequently used in combination with dexamethasone to prevent the acute inflammatory reaction due to cysticercal death. It has been reported that dexamethasone increases the plasma level of albendazole sulfoxide, the active metabolite of albendazole. The pharmacokinetic interaction of albendazole sulfoxide with dexamethasone, associated or not with cimetidine, was investigated in 24 patients with active intraparenchymal brain cysticercosis. Eight of these patients received albendazole alone, eight received it in combination with dexamethasone, and eight received it in combination with both dexamethasone and cimetidine. The pharmacokinetic parameters maximum plasma concentration, time to maximum plasma concentration, absorption half-life, and absorption rate constant did not differ between groups, suggesting that the formation of albendazole sulfoxide was not altered by the administration of dexamethasone, combined or not with cimetidine. There were significant differences, however, in the parameters plasma concentration-time curve, oral clearance, elimination half-life, and elimination rate constant, suggesting that dexamethasone, combined or not with cimetidine, decreases the rate of elimination of albendazole sulfoxide.