Chapters authored
Impact of Severe Sepsis or Septic Shock on Drug Response
Part of the book: Severe Sepsis and Septic Shock
Therapeutic Monitoring of Anticonvulsants: Use of Saliva as Biological Fluid
Plasma drug concentration is not homogeneous within the intravascular space, being the arterial (PA) concentrations higher or lower than that in veins (PV) depending on whether the samples are taken during the drug absorption or the elimination phases, respectively. However, blood samples are currently withdrawn from peripheral veins and total (bound plus unbound) plasma drug concentration is assayed. Despite the fact that free plasma drug levels (PfV) are not determined in routine therapeutic drug monitoring (TDM), they could be assayed for research purposes. Salivary drug concentrations (S) approximate to their free plasma levels in the arteries of the great circulation. Saliva is recommended to be collected with stimulation to minimize the difference between the pHs of both fluids (saliva and blood), and thus, artery/vein-free drug concentration ratios (PfA/PfV) could be surrogated by the stimulated saliva/free-plasma in vein drug concentration ratios (SS/PfV). It is possible in this way not only to assess this S/P ratio but also to infer the brain (B)/PfV ratio, which is actually the most relevant for antiepileptic drugs (AEDs). Different cases of AEDs are considered in this review, taking into account their physiochemical properties and their ability to be transported by membrane carriers.
Part of the book: Epileptology
Active Pharmacovigilance in Epileptic Patients: A Deep Insight into Phenytoin Behaviour
Despite the introduction of new and more expensive anticonvulsant drugs, phenytoin (PHT) is still a first-line medication for common types of epilepsy such as tonic-clonic and complex partial seizures but not for absence seizures. PHT shows a nonlinear kinetics and a narrow therapeutic range, thus a fine balance must be found between efficacy and toxic effects. Since the free (unbound) drug is responsible for producing the pharmacological effect, the concentration in a novel biological fluid more closely related to arterial free plasma drug concentration—saliva—is used in this study as part of the monitoring strategy. Therefore, in order to optimize therapy in epileptic patients under PHT treatment, plasma and saliva concentrations of PHT were measured, and adverse drug reactions were registered during a 2-year follow-up. CYP2C9, CYP2C19, and epoxide hydrolase polymorphisms (enzymes involved in PHT metabolism) were also analyzed using, in this way, pharmacogenetics for drug safety. The two PHT brands commercially available in our country and used in this study demonstrated similar pattern of efficacy and safety.
Part of the book: Pharmacovigilance
Revisiting Pharmacokinetics and Pharmacogenetics of Methadone in Healthy Volunteers
Methadone acts as a μ opioid agonist, a serotonin and norepinephrine reuptake inhibitor, and a noncompetitive N-methyl-D-aspartate receptor antagonist. These actions altogether are responsible for its efficacy in the management of chronic pain. It is available as a racemic mixture of (R)- and (S)-methadone, both being stereoisomers responsible for its analgesic effect. Methadone elimination occurs mainly through metabolism in the liver by CYP3A4, CYP2B6, and CY2C19 and to a lesser extent by CYP2D6 and in the intestine by CYP3A4. The relative intestinal content of CYP2B6 and CY2C19 is unknown but it seems that CYP2B6 is not present at the intestine. CYP3A4, CYP2B6, and CYP2C19 convert methadone mainly into 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine(EDDP). CYP2B6 and CYP2C19 are stereoselective to S- and R-enantiomer, respectively. The pharmacokinetic study carried out in healthy volunteers by our research group confirmed that MTD undergoes recirculation via gastric secretion and intestinal reabsorption and revealed that the drug is extensively metabolized in the liver but intestinal metabolism is not only relevant but also stereoselective. Polymorphisms of the CYP2B6 and CYP2C19 isoenzymes and their relationship with the pharmacokinetics of MTD were also assessed.
Part of the book: Drug Discovery and Development