Hydroxylation and N-dechloroethylation of Ifosfamide and deuterated Ifosfamide by the human cytochrome p450s and their commonly occurring polymorphisms.

The hydroxylation and N-dechloroethylation of deuterated ifosfamide (d4IFO) and ifosfamide (IFO) by several human P450s have been determined and compared. d4IFO was synthesized with deuterium at the alpha and alpha' carbons to decrease the rate of N-dechloroethylation and thereby enhance hydroxylation of the drug at the 4' position. The purpose was to decrease the toxic and increase the efficacious metabolites of IFO. For all of the P450s tested, hydroxylation of d4IFO was improved and dechloroethylation was reduced as compared with nondeuterated IFO. Although the differences were not statistically significant, the trend favoring the 4'-hydroxylation pathway was noteworthy. CYP3A5 and CYP2C19 were the most efficient enzymes for catalyzing IFO hydroxylation. The importance of these enzymes in IFO metabolism has not been reported previously and warrants further investigation. The catalytic ability of the common polymorphisms of CYP2B6 and CYP2C9 for both reactions were tested with IFO and d4IFO. It was determined that the commonly expressed polymorphisms CYP2B6*4 and CYP2B6*6 had reduced catalytic ability for IFO compared with CYP2B6*1, whereas CYP2B6*7 and CYP2B6*9 had enhanced catalytic ability. As with the wild-type enzymes, d4IFO was more readily hydroxylated by the polymorphic variants than IFO, and d4IFO was not dechloroethylated by any of the polymorphic forms. We also assessed the use of specific inhibitors of P450 to favor hydroxylation in human liver microsomes. We were unable to separate the pathways with these experiments, suggesting that multiple P450s are responsible for catalyzing both metabolic pathways for IFO, which is not observed with the closely related drug cyclophosphamide.

Pharmacogenetic considerations in the elderly patient.

OBJECTIVE: To outline how the inclusion of pharmacogenetic data lends additional information in the overall decision making relative to drug therapy in the elderly patient. DATA SOURCES: The National Center for Biotechnology's PubMed database was searched for relevant pharmacogenetic-based dosing guidelines, as well as papers discussing drug use, and pharmacogenetics in the elderly. Google Scholar was also searched for the related documents. STUDY SELECTION: Papers cited were those that presented a rationale for drug therapy in the elderly, presented pharmacogenetic-based dosing guidelines with supporting information, and specifically discussed pharmacogenetics and other therapeutic principles relative to drug therapy in the elderly. DATA SYNTHESIS: Specific examples were extracted for presentation where data on drug use in the elderly corresponded with pharmacogenetic information. Specific examples were selected to illustrate pharmacogenetic influences on medications of clinical significance in the elderly population including meperidine, tramadol, amitriptyline, nortriptyline, flecainide, and propafenone. These medications were identified as intersecting points in the Beers criteria and pharmacogenetic guidelines provided by the Clinical Pharmacogenetics Implementation Consortium and the Dutch Pharmacogenetics Working Group, or where mechanisms of pharmacogenetic influences were applicable. CONCLUSIONS: Inclusion of pharmacogenetic data/information in the decision-making process may help the clinician to more appropriately guide therapy in the elderly patient.

An interprofessional education experience to promote the role of the pharmacist in precision medicine.

BACKGROUND: An interprofessional (IP) experience was created that demonstrated the roles and responsibilities of pharmacists and physicians in clinical implementation of pharmacogenomics (PGx). The IP experience focused on PGx-themed patient cases and application of genotyping results to drug therapy management. INTERPROFESSIONAL EDUCATION ACTIVITY: In 2016 and 2017, third-year pharmacy students and first-year medical students were placed on interprofessional teams with two to three students each. The teams resolved PGx patient cases, medical students wrote prescriptions for altered drug therapy based on the PGx profiles of the patients, and pharmacy students assessed and provided feedback to medical students about the prescriptions. Student could also volunteer to be genotyped for CYP2C19*2, and the results were compared. DISCUSSION: The IP experience significantly enhanced PGx knowledge and increased the confidence of using PGx in patient cases for the majority of participants. The experience did not increase the recognition of each discipline's role in precision medicine in a statistically significant manner. Accurate prescription writing was challenging for the first-year medical students (44.3% prescriptions written correctly). The genotyping results did not deviate from a Hardy Weinberg equilibrium for this population. IMPLICATIONS: IP experiences focused on PGx present an ideal opportunity to educate and initiate collaborations between pharmacists and physicians and to promote utilization of PGx in precision medicine. The roles and responsibilities for each discipline can be easily recreated in an IP experience to provide robust training to the students.

A review of the influence of functional group modifications to the core scaffold of synthetic cathinones on drug pharmacokinetics.

RATIONALE: The synthetic cathinones are a class of designer drugs of abuse that share a common core scaffold. The pharmacokinetic profiles of the synthetic cathinones vary based on the substitutions to the core scaffold. OBJECTIVES: To provide a summary of the literature regarding the pharmacokinetic characteristics of the synthetic cathinones, with a focus on the impact of the structural modifications to the pharmacokinetics. RESULTS: In many, but not all, instances the pharmacokinetic characteristics of the synthetic cathinones can be reasonably predicted based on the substitutions to the core scaffold. Mephedrone and methylone are chemically alike and have similar Tmax and t1/2 in male rats. MDPV, a structurally distinct synthetic cathinone from mephedrone and methylone, has a lower Tmax and t1/2. Increasing the length of the alkyl chain on the α position of methylone, to produce pentylone, results in increased plasma concentrations and longer t1/2. Metabolism of the synthetic cathinones is reasonably predictable based on the chemical structure, and several phase I metabolites retain pharmacodynamic activity. CYP2D6 is implicated in the metabolism of all of the synthetic cathinones, and other P450s (CYP1A2, CYP2B6, and CYP2C19) are known to contribute variably to the metabolism of specific synthetic cathinones. CONCLUSIONS: Continued research will lead to a better understanding of the pharmacokinetic changes associated with structural modifications to the cathinone scaffold, and potentially in the long range, enhanced overdose and addiction therapy. Additionally, the areas of polydrug use and pharmacogenetics have been largely overlooked with regard to synthetic cathinones.

Food restriction alters N'-propyl-4,5,6,7-tetrahydrobenzothiazole-2,6-diamine dihydrochloride (pramipexole)-induced yawning, hypothermia, and locomotor activity in rats: evidence for sensitization of dopamine D2 receptor-mediated effects.

Food restriction enhances sensitivity to the reinforcing effects of a variety of drugs of abuse including opiates, nicotine, and psychostimulants. Food restriction has also been shown to alter a variety of behavioral and pharmacological responses to dopaminergic agonists, including an increased sensitivity to the locomotor stimulatory effects of direct- and indirect-dopamine agonists, elevated extracellular dopamine levels in responses to psychostimulants, as well as suppression of agonist-induced yawning. Behavioral and molecular studies suggest that augmented dopaminergic responses observed in food-restricted animals result from a sensitization of the dopamine D2 receptor; however, little is known about how food restriction affects dopamine D3 receptor function. The current studies were aimed at better defining the effects of food restriction on D2 and D3 receptor function by assessing the capacity of N'-propyl-4,5,6,7-tetrahydrobenzothiazole-2,6-diamine dihydrochloride (pramipexole) to induce yawning, penile erection (PE), hypothermia, and locomotor activity in free-fed and food-restricted rats. Food restriction resulted in a suppression of pramipexole-induced yawning, a sensitized hypothermic response, and an enhanced locomotor response to pramipexole, effects that are suggestive of an enhanced D2 receptor activity; no effect on pramipexole-induced PE was observed. Antagonist studies further supported a food restriction-induced enhancement of the D2 receptor activity because the D2 antagonist 3-[4-(4-chlorophenyl)-4-hydroxypiperidin-l-yl]methyl-1H-indole (L741,626) recovered pramipexole-induced yawning to free-fed levels, whereas yawning and PE were suppressed following pretreatment with the D3 antagonist N-{4-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-trans-but-2-enyl}-4-pyridine-2-yl-benzamide hydrochloride (PG01037). The results of the current studies suggest that food restriction sensitized rats to the D2-mediated effects of pramipexole while having no effect on the D3-mediated effects of pramipexole.

P&T and Me.

Very few occasions bring more stress to a faculty member than the promotion and/or tenure (P&T) process. In this commentary, two recent chairs of P&T committees give their advice to future petitioners. Subtopics of the editorial discuss knowing the expectations, finding mentors to guide you, understanding the role of peer reviewers and preparing your dossier.