Corrigendum to: Determination of Cytochrome P450 Isoenzyme 2D6 (CYP2D6) Genotypes and Pharmacogenomic Impact on Primaquine Metabolism in an Active-Duty US Military Population
Michele SpringJason SousaQigui LiChristian A. DarkoMeshell N MorrisonSean R. MarcsisinKristin T MillsBrittney PotterKristopher PaolinoPatrick TwomeyJames E. MoonDonna ToshSusan CicatelliJeffrey W. FroudeBrandon PybusThomas G OliverWilliam F. McCarthyNorman C. WatersPhilip L. SmithGregory A. ReichardJason W. Bennett
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We aim to study the effects of CYP2D6 variants and drug-drug interaction on the metabolism of dacomitinib. CYP2D6 variants were incubated with 25-1000 μM dacomitinib for 40 min at 37 °C, and the reaction was terminated by cooling to -80 °C immediately. For an in vivo experiment, 18 male Sprague-Dawley rats were randomly divided into three groups (n = 6): a single dose of 5 mg/kg dacomitinib (group A), a single dose of 6 mg/kg trazodone (group B), and a combined group (group C). Processed samples were analyzed by ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS.) The relative clearance of dacomitinib was reduced for most of the variants. Moreover, the inhibitory potency of classic CYP inhibitors on dacomitinib metabolism was significantly different among the main subtypes of CYP2D6. Interestingly, compared with gefitinib, even the same CYP2D6 variants showed significant differences in metabolic activity, suggesting that the activity of CYP2D6 has strong variability. In addition, the interaction between trazodone and dacomitinib was determined both in vitro and in vivo. When dacomitinib was given in combination with trazodone, the blood exposure to these two drugs increased remarkably. The mechanistic study revealed that the interaction followed the noncompetitive inhibition. We demonstrated that the activity of CYP2D6 variants to metabolize dacomitinib was significantly reduced. In combination with the CYP2D6 inhibitor, the degree of activity inhibition of different variants obviously differed. When trazodone and dacomitinib were used in combination, the body exposure to the two drugs increased significantly. This study provides data for the precise use of dacomitinib in clinical settings.
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Characterization of the pharmacokinetic properties of the enantiomers of primaquine and carboxyprimaquine following administration of racemic primaquine given alone and in combination with commonly used antimalarial drugs. Enantiomeric pharmacokinetics were evaluated in 49 healthy adult volunteers enrolled in three randomized cross-over studies in which a single dose of primaquine was given alone and then, after a suitable washout period, in combination with chloroquine, dihydroartemisinin/piperaquine or pyronaridine/artesunate. Non-linear mixed-effects modelling was used to characterize pharmacokinetics and assess the impact of drug–drug interactions. The volume of distribution of racemic primaquine was decreased by a median (95% CI) of 22.0% (2.24%–39.9%), 24.0% (15.0%–31.5%) and 25.7% (20.3%–31.1%) when co-administered with chloroquine, dihydroartemisinin/piperaquine and pyronaridine/artesunate, respectively. The oral clearance of primaquine was decreased by a median of 19.1% (14.5%–22.8%) when co-administered with pyronaridine/artesunate. These interactions were enantiospecific with a relatively higher effect on (+)-S-primaquine than on (−)-R-primaquine. No drug–drug interaction effects were seen on the pharmacokinetics of either carboxyprimaquine enantiomer. Population pharmacokinetic models characterizing the enantiospecific properties of primaquine were developed successfully. Exposure to primaquine, particularly to the (+)-S-primaquine but not the carboxy metabolites, increased by up to 30% when co-administered with commonly used antimalarial drugs. A better mechanistic understanding of primaquine metabolism is required for assessment of its efficacy and haematological toxicity in humans.
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ABSTRACT Primaquine is an important therapeutic resource for malaria treatment and it has wide activity against several pathogens. The haematotoxicity of primaquine is the major problem for its therapeutic application. This effect is aggravated by repeated use at high doses and by the wide fluctuation of plasma levels after administration. The primaquine prodrug (Phe‐Ala‐PQ) was planned in order to modify the pharmacokinetics and toxicity of primaquine. The in vitro conversion of Phe‐Ala‐PQ to primaquine, and the primaquine pharmacokinetics were evaluated in four groups of rats: two groups that received a single dose of Phe‐Ala‐PQ, one by intravenous and the other by gavage route, and two other groups that received primaquine diphosphate, by intravenous and gavage routes. In addition, the erythrocyte osmotic fragility was compared in two groups of rats that received multiple doses of primaquine diphosphate or Phe‐Ala‐PQ, as a parameter of haematotoxicity. The in vitro conversion of Phe‐Ala‐PQ to primaquine by plasma enzyme action was observed. The pharmacokinetic profile of primaquine from Phe‐Ala‐PQ was more favourable due to the lower fluctuation of plasma concentrations. Haematotoxicity was not evidenced in the prodrug administration. The results reinforce the need for further studies with this prodrug, promising an alternative in the therapeutic use of primaquine. Copyright © 2012 John Wiley & Sons, Ltd.
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Global ambitions to eliminate malaria are intensifying, underscoring a critical need for transmission blocking tools. In 2012, the WHO recommended the use of 0.25 mg/kg of single low-dose (SLD) primaquine to stop Plasmodium falciparum transmission. To ensure the availability of SLD primaquine to countries in need of this tool, more information on the supply, programmatic, and regulatory barriers to the rollout of SLD primaquine is required.
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Abstract Primaquine is a gametocytocidal drug known to significantly reduce malaria transmission. However, primaquine induces a dose-dependent acute hemolytic anemia (AHA) in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency that has led to a limited use of the drug especially in Africa where the condition is common. The World Health Organization (WHO) now recommends a single low dose (SLD) of primaquine (0.25 mg/kg) as P. falciparum gametocytocidal without the need for prior screening of G6PD status. Adoption and implementation of SLD primaquine in Africa may probably reduce malaria transmission, a pre-requisite for malaria elimination. This review therefore, focused on the safety of primaquine for control of malaria in Africa. The literature search was performed using online database Google Scholar, PubMed, HINARI, and Science Direct. Search terms used were “malaria”, “primaquine”, “safety”, “G6PD deficiency”, “large scale” or “mass administration”. Clinical trials in many African countries have shown SLD primaquine to be safe especially in a milder African G6PD A- variant. Likewise, large-scale primaquine administrations outside Africa involving hundreds of thousands to tenths of millions of participants and with severe variants of G6PD deficiency have also shown primaquine to be safe and well-tolerated. Fourteen deaths associated with primaquine have been reported globally over the past 6 decades, but none occurred following the administration of SLD primaquine. Available evidence shows that the WHO-recommended SLD primaquine dose added to effective schizonticides is safe and well-tolerated even in individuals with G6PD deficiency, and therefore, it can be safely used in the African population with the mildest G6PD A- variant.
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Malaria is divided into two types, namely erythrocytic and hepatic
malaria. Primaquine (PQ), which belongs to the 8-aminoquinoline group,
is the only effective antimalarial drug in the hepatic phase, but this drug
has the effect of hemolytic anemia in patients with glucose-6-Phosphate
dehydrogenase (G6PDase) deficiency. Chloroquine also has potent
activity against the asexual stage (erythrocytic stage), but has no activity
against hypnozoites. The use of primaquine with chloroquine in therapy
has been reported to increase the effectiveness of primaquine and can
reduce the toxicity of primaquine. In this research, biodistribution tests
were carried out in vivo on liposome primaquine and chloroquine
liposome mice and combinations compared chloroquine. Liposomes and
free drugs injected equivalent to doses of primaquine and chloroquine,
which are 3.5 mg and 1.8 mg / kg BB mice. After 24 hours of drugs
administration, the blood level of primaquine and chloroquine wiil be
determination using HPLC. The result shored about 86,21% anf 72,92%
injected dose of chloroquine were observe for liposome chloroquine and
liposome combination of chloroquine and primaquine, while it is only
14,62% detected after free drugs administration. An the other hand ,
primaquine not be quantified because no specific read well before during
the analysis. It can be that the chloroquine drug in the preparation of
liposomes has proven effective compared to free drug, as evidence condition liposome could improve systemic blood syrculation of
chloroquine.
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Cytochrome P450 enzymes are essential for the metabolism of many medications. Although this class has more than 50 enzymes, six of them metabolize 90 percent of drugs, with the two most significant enzymes being CYP3A4 and CYP2D6. Genetic variability (polymorphism) in these enzymes may influence a patient's response to commonly prescribed drug classes, including beta blockers and antidepressants. Cytochrome P450 enzymes can be inhibited or induced by drugs, resulting in clinically significant drug-drug interactions that can cause unanticipated adverse reactions or therapeutic failures. Interactions with warfarin, antidepressants, antiepileptic drugs, and statins often involve the cytochrome P450 enzymes. Knowledge of the most important drugs metabolized by cytochrome P450 enzymes, as well as the most potent inhibiting and inducing drugs, can help minimize the possibility of adverse drug reactions and interactions. Although genotype tests can determine if a patient has a specific enzyme polymorphism, it has not been determined if routine use of these tests will improve outcomes.
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This paper presents the pharmacokinetic properties of newer second generation antidepressants, with an emphasis on the main metabolic pathways of drugs and metabolites as well as their effects on the cytochrome P450 enzymes. Except for Milnacipran all newer antidepressants are biotransformed in the presence of at least one cytochrome P450 izoenzyme. Drugs and their metabolites may be the substrates or inhibitors of cytochromes P450. The knowledge of drugs' metabolic pathways as well as the knowledge of substrates and inhibitors of izoenzymes assists in choice of a proper drug and its dose. It is particularly important in case of polypharmacotherapy when there is a high risk of adverse events. It is also important to remember about genetic polymorphism of some cytochrome P450 izoenzymes (CYP2D6, CYP2C19) that underlies the marked inpatient variability in drug metabolism.
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Letter in regards to: Del Re M, Rofi E, Citi V, Fidilio L, Danesi R. Should CYP2D6 be genotyped when treating with tamoxifen? Pharmacogenomics 17(18), 1967-1969 (2016). In response to: Damkier P. Don't think twice it's all right: tamoxifen and CYP2D6 genotyping in the treatment of breast cancer patients. Pharmacogenomics 18(8), XXX (2017).
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