Volume 30, Issue 1

Venlafaxine (VEN) is an antidepressant agent widely used nowadays as an alternative to selective serotonin reuptake inhibitors (SSRIs), particularly for the treatment of SSRI-resistant depression. As the co-administration of antidepressant drugs with other medications is very common in clinical practice, the potential risk for pharmacokinetic and/or pharmacodynamic drug interactions that may be clinically meaningful increases. Bearing in mind that VEN has exhibited large variability in antidepressant response, besides the individual genetic background, several other factors may contribute to those variable clinical outcomes, such as the occurrence of significant drug-drug interactions. Indeed, the presence of drug interactions is possibly one of the major reasons for interindividual variability, and their anticipation should be considered in conjugation with other specific patients’ characteristics to optimize the antidepressant therapy. Hence, a comprehensive overview of the pharmacokinetic- and pharmacodynamic-based drug interactions involving VEN is herein provided, particularly addressing their clinical relevance.

Ethnicity is one of the major factors involved in interindividual variability to drug response. This study aims to describe the frequency of the most relevant pharmacogenetic biomarkers and metabolic phenotypes in Central American healthy volunteers and to determine its interethnic variability. Twenty-six original research articles on allelic, genotypes or metabolic phenotype frequencies were analyzed, in which a total number of 7611 Central American healthy volunteers were included (6118 were analyzed for genotype and 1799 for metabolic phenotype). No reports were available for population from Belize and Honduras. The CYP2D6*4 and *5 frequencies in Amerindian populations from Costa Rica have shown to be among the highest frequencies so far reported in the world. Furthermore, NAT2*5 and *6 presented higher frequencies in admixed populations than in Amerindians, but, inversely, the NAT2*7 was more frequent in Amerindians compared to an admixed population. Likewise, different patterns of distribution have been shown in HLA-A*02 , *03 and HLA-B*07 among Native populations from Latin America. Reports on Central American populations were also found for the CYP2C19, LDLR , CYP2E1 , MDR1 , G6PD , TP53 , CYP1A2, CYP3A4 and CYP3A5 biomarkers, but no data were available for the other 91 pharmacogenetic biomarkers revised in Central American populations. Differences in the frequency of some pharmacogenetic biomarkers and metabolic phenotypes were found, showing interethnic variability within Central American and with other Latin American populations.

Pharmacogenetics is being applied to develop individual specific therapies considering different ethnic groups and mixed populations. The Venezuelan population is very heterogeneous as a result of the admixture process that occurred between Native Americans, Europeans, and Africans through five centuries. This review provides a summary of the literature concerning gene variants within drug-metabolizing enzymes, drug targets, and drug receptors ( CYP2C19 , CYP2D6 , GSTM1 , GSTT1 , GSTP1 , NAT2 , MTHFR , LEP , LEPR , LTC4S , and ADRβ2 genes) evaluated in the Venezuelan population. In particular, most of the studies were conducted with relatively low numbers of individuals. Some of these studies included analyses of genetic polymorphisms in native groups living in this country. Although the recent studies represent a hopeful progress toward the inclusion of the Venezuelan population among those who will benefit from the implementation of pharmacogenetic principles and tools in drug therapy, there are not yet sufficient data concerning allelic frequencies of genomic biomarkers related to drug response for their implementation in clinical practice. Therefore, there is a critical need for more research in pharmacogenetics in Venezuela to increase data availability.

Background: Interindividual variability exists in statin lipid-lowering response, partially attributed to genetic factors. CYP3A4 intron 6 C>T polymorphism ( CYP3A4*22 allele, rs35599367) has been recently identified and was associated with reduced CYP3A4 expression. We analyzed the association of CYP3A4*22 allele with response to atorvastatin and simvastatin. Methods: A total of 416 statin-treated (207 atorvastatin- and 209 simvastatin-treated) adults with primary hypercholesterolemia were included in the study. Total cholesterol and low-density lipoprotein cholesterol were measured at baseline and on 6 months of treatment. CYP3A4*22 allele was analyzed with TaqMan assay. Results: In the entire cohort population, 41 individuals carried CYP3A4*22 allele (18 in atorvastatin and 23 in simvastatin treatment). CYP3A4*22 allele was not associated with lipid-lowering response to atorvastatin or simvastatin. No sex-gene or statin dose-gene interaction was observed in either statin-treated patient cohort. Conclusions: The effect of CYP3A4*22 allele on lipid-lowering response to CYP3A metabolized statins, if present, can potentially be masked by relevant confounding or uncontrolled factors; therefore, further population-driven studies are required.

Background: Chloral hydrate (CH), a sedative and metabolite of the environmental contaminant trichloroethylene, is metabolized to trichloroacetic acid, trichloroethanol, and possibly dichloroacetate (DCA). DCA is further metabolized by glutathione transferase zeta 1 (GSTZ1), which is identical to maleylacetoacetate isomerase (MAAI), the penultimate enzyme in tyrosine catabolism. DCA inhibits its own metabolism through depletion/inactivation of GSTZ1/MAAI with repeated exposure, resulting in lower plasma clearance of the drug and the accumulation of the urinary biomarker maleylacetone (MA), a metabolite of tyrosine. It is unknown if GSTZ1/MAAI may participate in the metabolism of CH or any of its metabolites and, therefore, affect tyrosine catabolism. Stable isotopes were utilized to determine the biotransformation of CH, the kinetics of its major metabolites, and the influence, if any, of GSTZ1/MAAI. Methods: Eight healthy volunteers (ages 21–40 years) received a dose of 1 g of CH (clinical dose) or 1.5 μg/kg (environmental) for five consecutive days. Plasma and urinary samples were analyzed by gas chromatography-mass spectrometry. Results: Plasma DCA (1.2–2.4 μg/mL), metabolized from CH, was measured on the fifth day of the 1 g/day CH dosage but was undetectable in plasma at environmentally relevant doses. Pharmacokinetic measurements from CH metabolites did not differ between slow and fast GSTZ1 haplotypes. Urinary MA levels increased from undetectable to 0.2–0.7 μg/g creatinine with repeated CH clinical dose exposure. Kinetic modeling of a clinical dose of 25 mg/kg DCA administered after 5 days of 1 g/day CH closely resembled DCA kinetics obtained in previously naïve individuals. Conclusions: These data indicate that the amount of DCA produced from clinically relevant doses of CH, although insufficient to alter DCA kinetics, is sufficient to inhibit MAAI and tyrosine catabolism, as evidenced by the accumulation of urinary MA.

Background: Bosutinib is an orally bioavailable dual Src/Abl tyrosine kinase inhibitor and a CYP3A4 enzyme substrate. This study assessed the safety, tolerability, and pharmacokinetics of bosutinib when coadministered with the CYP3A4 inducer rifampin in 24 healthy men. Methods: Subjects received single oral doses of bosutinib 500 mg (Days 1 and 14) and once-daily oral doses of rifampin 600 mg (Days 8–17); serial blood samples were analyzed. Results: Bosutinib exposures were reduced following concomitant administration of rifampin vs. bosutinib alone, measured by peak plasma concentration (C max ; 112 vs. 16.0 ng/mL; 86% reduction), total area under the concentration-time curve (AUC; 2740 vs. 207 ng·h/mL; 92% reduction), and AUC to the last measurable concentration at time T (2440 vs. 158 ng·h/mL; 94% reduction). Median time to C max and mean half-life were shorter for bosutinib plus rifampin vs. single-agent bosutinib. Oral clearance increased approximately 13-fold; the volume of distribution increased from 9560 to 72,900 L. Treatment-emergent adverse events appeared less frequently with bosutinib plus rifampin (59%) vs. single-agent bosutinib (79%); diarrhea was reported in 11 (46%) vs. 4 (18%) subjects, respectively. Conclusions: Concomitant use of potent or moderate CYP3A inducers with bosutinib should be avoided because of the effects of drug-drug interaction observed between bosutinib and rifampin.

Background: Lithium, which is often used for the treatment of bipolar disorders, is mainly recovered into urine after being orally administered. Due to the fact that it is completely absorbed via the gastrointestinal tract, it remains unknown whether biliary excretion is involved in the lithium disposition. In this study, we examined biliary excretion of lithium in rats and compared these with renal excretion. Materials and methods: After the injection of lithium chloride to femoral vein, plasma levels and excretion into urine and bile of lithium were evaluated. Results: After its intravenous administration as a bolus, the plasma concentration of lithium decreased time-dependently. Until 60 min, 6.47% and 0.694% of injected lithium were excreted into urine and bile, respectively. The biliary clearance of lithium was calculated to be 0.0779 mL/min/kg, and this was 11.3% of the renal clearance. Conclusions: These findings suggest the low ability of the liver to eliminate lithium from plasma in comparison with the kidney in rats.

Succinylcholine is one of the most commonly used drugs by anesthesiologists worldwide for rapid access to airway both in emergency and elective situations. Nonetheless, the very mention of succinylcholine generates the most energetic high decibel debate between its users and nonusers. Despite its potential to produce a short-acting, ultra-intense neuromuscular block rapidly in seconds, it is surrounded by a plethora of side effects and drug interactions. This case report is about one such drug interaction of this innocent yet malicious drug, which resulted in the death of a 14-year-old girl. Both β-adrenergic blockers and succinylcholine are known to cause hyperkalemia. Life-threatening hyperkalemia in susceptible individuals who have been administered succinylcholine has the most severe effect on the myocardium and can result in asystole with minimal chances of resuscitation. Both succinylcholine and a nonselective β-adrenergic blocker, propranolol, have the propensity to affect the transcellular redistribution of potassium which can result in hyperkalemia. We advocate cautious use of this drug combination till further studies confirm the drug interaction and find the potential triggering factors involved.