Sonia Gallego-Sandín

Effects of CYP2D6 Genotype on the Pharmacokinetics, Pharmacodynamics, and Safety of Risperidone in Healthy Volunteers

The objective of this study was to analyze the relationship between CYP2D6 genotype and pharmacokinetics and pharmacodynamics of risperidone. Seventy-one healthy volunteers (36 women and 35 men) received a 1-mg single oral dose of risperidone. Six major CYP2D6 polymorphisms (CYP2D6*3, *4, *5, *6, *7, and *9) and the duplication were detected. Subjects were classified into 4 phenotypic groups: 6 ultrarapid (UMs), 34 extensive (EMs), 25 intermediate (IMs), and 6 poor metabolizers (PMs). There was a clear relationship between the number of active alleles and the pharmacokinetic parameters for risperidone and 9-hydroxyrisperidone, but there were no differences for total active moiety. Area under the curve and half-life of risperidone were significantly higher in PMs and IMs compared with EMs and UMs, which showed higher area under the curve of 9-hydroxyrisperidone. Risperidone produced a small decrease in blood pressure, a mild increase in QTc and a quick increase in prolactin, without significant differences between groups. Surprisingly, the incidence of adverse reactions was lower in PMs (50%) than in other subjects (78%). In conclusion, metabolism of risperidone depends on the number of active CYP2D6 alleles. So, PM subjects show higher concentrations of risperidone and very low concentrations of 9-hydroxyrisperidone. On the contrary, EM and UM subjects show low concentrations of risperidone and high concentrations of 9-hydroxyrisperidone. However, no major pharmacodynamic differences are observed between CYP2D6 genotypes, presumably because of the similar pharmacological activity of parent drug and metabolite.

Influence of CYP2C8 and CYP2C9 polymorphisms on pharmacokinetic and pharmacodynamic parameters of racemic and enantiomeric forms of ibuprofen in healthy volunteers.

OBJECTIVES (i) To define the incidence of alleles CYP2C8*1 to *5 in a Spanish population; (ii) to test the impact of such alleles, and those of CYP2C9, on the metabolism of racemic ibuprofen, R-ibuprofen and S-ibuprofen; and (iii) to discern whether those metabolic alterations have safety implications. METHODS Data from three phase I clinical trials with 69 healthy volunteers taken ibuprofen were analyzed. Genotyping were performed by PCR. Pharmacokinetic parameters were determined in studies 1 and 2 by non-compartmental analysis. Levels of COX-1, COX-2, eNOS and iNOS were determined by Western Blots in gastric biopsies of study 3. RESULTS Allelic frequencies were 0.80, 0.02, 0.11, 0.07 and 0 for CYP2C8*1, *2, *3, *4 and *5. CYP2C9*3 allele had a decreased racemic ibuprofen metabolism, leading to a 30% augmentation of AUC(0-infinity) and a 30% reduction of clearance compared to CYP2C9*1 (p < 0.05). CYP2C8*3 had a 20% augmentation of clearance compared to CYP2C8*1 (p < 0.05) of R-ibuprofen. CYP2C9*3 had a 45% reduction of clearance, as well as a 87% and 47% augmentation of AUC(0-infinity) and t(1/2) with respect to CYP2C9*1 of S-ibuprofen and a 30% reduction of clearance of R-ibuprofen. A decreased iNOS expression was found in CYP2C8*3 compared to wild type (p < 0.05). Adverse events in CYP2C8*3 (20%) and *4 (20%) were fewer than in CYP2C8*1 (77%). CONCLUSIONS This study suggest an impaired metabolism of racemic, S-ibuprofen and R-ibuprofen in CYP2C9*3; an increased R-ibuprofen metabolism in CYP2C8*3; and fewer adverse events in CYP2C8*3 volunteers; that correlates with a decreased expression of iNOS.

Gender differences in angiotensin-converting enzyme (ACE) activity and inhibition by enalaprilat in healthy volunteers.

Abstract: This bioequivalence study was supported by Laboratorios Vita S.A (Barcelona). To study the existence of differences between sexes in the pharmacokinetic and pharmacodynamic of enalapril. A bioequivalence phase 1 clinical trial to compare two formulations of enalapril was carried out in twenty-four healthy volunteers (12 men and 12 women). Enalaprilat concentrations, plasma activity of ACE, and systolic and diastolic arterial pressure were determined. Basal activity of ACE and the maximum ACE inhibition were significantly smaller in women. No significant differences in the drug concentration required to produce 50% of Emax were observed. Women had lower systolic arterial pressures and ACE activities than men at any time, even when the maximum inhibition of the ACE activity was attained. Women at the follicular phase had a minimum activity of ACE significantly inferior than men. Healthy women had lower systolic arterial pressures and ACE activities than men.

Bcl2 mitigates Ca2+ entry and mitochondrial Ca2+ overload through downregulation of L-type Ca2+ channels in PC12 cells

Altered calcium homeostasis and increased cytosolic calcium concentrations ([Ca2+]c) are linked to neuronal apoptosis in epilepsy and in cerebral ischemia, respectively. Apoptotic programmed cell death is regulated by the antiapoptotic Bcl2 family of proteins. Here, we investigated the role of Bcl2 on calcium (Ca2+) homeostasis in PC12 cells, focusing on L-type voltage-dependent calcium channels (VDCC). Cytosolic Ca2+ transients ([Ca2+]c) and changes of mitochondrial Ca2+ concentrations ([Ca2+]m) were monitored using cytosolic and mitochondrially targeted aequorins of control PC12 cells and PC12 cells stably overexpressing Bcl2. We found that: (i) the [Ca2+]c and [Ca2+]m elevations elicited by K+ pulses were markedly depressed in Bcl2 cells, with respect to control cells; (ii) such depression of [Ca2+]m was not seen either in digitonin-permeabilized cells or in intact cells treated with ionomycin; (iii) the [Ca2+]c transient depression seen in Bcl2 cells was reversed by shRNA transfection, as well as by the Bcl2 inhibitor HA14-1; (iv) the L-type Ca2+ channel agonist Bay K 8644 enhanced K(+)-evoked [Ca2+]m peak fourfold in Bcl2, and twofold in control cells; (v) in current-clamped cells the depolarization evoked by K+ generated a more hyperpolarized voltage step in Bcl2, as compared to control cells. Taken together, our experiments suggest that the reduction of the [Ca2+]c and [Ca2+]m transients elicited by K+, in PC12 cells overexpressing Bcl2, is related to the reduction of Ca2+ entry through L-type Ca2+ channels. This may be due to the fact that Bcl2 mitigates cell depolarization, thus diminishing the recruitment of L-type Ca2+ channels, the subsequent Ca2+ entry, and mitochondrial Ca2+ overload.

Effect of Ibuprofen on Cyclooxygenase and Nitric Oxide Synthase of Gastric Mucosa: Correlation with Endoscopic Lesions and Adverse Reactions

The aim of this study was to evaluate the effect of ibuprofen on gastric mucosa and enzymes involved in gastroprotection in healthy volunteers. Twenty-four Helicobacter pylori-negative subjects were randomized to treatment with ibuprofen or ibuprofen–arginate (each 600 mg/6 hr during 3 days). Endoscopies were performed 1 week before and after treatment. Biopsies were taken from the gastric antrum and corpus for determination of prostaglandin E2 (PGE2) by ELISA and cyclooxygenase (COX-1 and COX-2) and nitric oxide synthase (eNOS and iNOS) by western blot. All subjects had at least one gastric lesion except for two individuals taking ibuprofen–arginate. Ibuprofen-arginate caused a lower rate of clinical adverse reactions than ibuprofen. Subjects with gastric lesions or adverse reactions had lower PGE2 levels. COX-1, COX-2, eNOS, and iNOS were detectable in all subjects. The constitutive enzymes (COX-1 and eNOS) did not change after treatment. COX-2 was higher in corpus than antrum and it increased after ibuprofen treatment. iNOS tended to increase mildly in the corpus in subjects with adverse reactions or endoscopic lesions. There were no significant differences between ibuprofen and ibuprofen–arginate in PGE2, or enzymes.

Pharmacokinetics and Pharmacodynamics of a Single Bolus of Propofol 2% in Healthy Volunteers

This study was undertaken to assess the bioequivalence between a new formulation of propofol 2% and the commercially available product Diprivan. Secondary objectives were to compare the times to onset of and emergence from hypnosis, the hemodynamic effects, and the safety profiles. Twelve healthy male volunteers were included in a randomized crossover study. Subjects were administered a 2‐mg/kg single bolus injection of each formulation separated by a 7‐ to 10‐day washout period. Plasma propofol was determined by reversed‐phase liquid chromatography with fluorescence detection. Eleven subjects completed the study, and both formulations were considered bioequivalent. There were no serious or severe adverse events. The concentration‐time profiles of all the subjects could adequately be described using a three‐compartment model. The mean times to cessation of counting out loud (17 vs. 18 s) and to eye opening (245 vs. 244 s) were not statistically different between treatment groups. Moreover, they seem to show some degree of pharmacodynamic bioequivalence, although a higher number of subjects are necessary to unequivocally demonstrate it.

The comparative hemodynamic effects of intravenous IQB‐9302 and bupivacaine in anesthetized rats

Background:  The new local anesthetic IQB‐9302 is an amide derivative bearing a cyclopropyl group, with remarkable long duration of action and relative low toxicity. In trying to characterize further its safety profile, the current study compared the hemodynamic effects of different concentrations of bupivacaine and IQB‐9302 with saline.