Drug Metabolism and Personalized Therapy

Published by De Gruyter

Volume 34 Issue 2

June 2019

Issue of Drug Metabolism and Personalized Therapy

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Contents
Journal Overview

Opinion Paper

May 30, 2019

Regulatory sciences and translational pharmacogenetics: amitriptyline as a case in point

Luana Mifsud Buhagiar, Benjamin Micallef, John Joseph Borg, Helen Vella, Anthony Serracino Inglott, Godfrey LaFerla

Article number: 20190005

Abstract

Regulatory developments and clinical implementation, or the lack thereof, are primary clinchers, in the enduring endeavors to realize the translational quality of pharmacogenetics. Here, we present the case of amitriptyline, an established drug with pharmacogenetic implications. The integration of pharmacogenetic information in the official product literature and throughout the evaluation of safety concerns is considered. In our opinion, apart from emboldening genomic research in drug development and the valid pursuit towards global harmonization in the field, it is rational to look into the applicability of the data we have today.

Original Articles

April 2, 2019

Drug S-oxidation and phenylalanine hydroxylase: a biomarker for neurodegenerative susceptibility in Parkinson’s disease and amyotrophic lateral sclerosis

Lucinda Rawlings, Laura Turton, Stephen C. Mitchell, Glyn B. Steventon

Article number: 20180038

Abstract

Background The S-oxidation of S-carboxymethyl-L-cysteine has been reported previously to be a biomarker of disease susceptibility in Parkinson’s disease and amyotrophic lateral sclerosis. In the present investigation, the original observations have been extended and confirmed. Methods Meta-analysis of previously published investigations into the S-oxidation polymorphism together with new subject data was evaluated. Results The incidence of the poor metaboliser phenotype (no urinary recovery of S-oxide metabolites) was found to be 3%–7% within healthy and non-neurological disease populations, whereas 38% of the Parkinson’s disease subjects and 39% of the amyotrophic lateral sclerosis group were phenotyped as poor metabolisers. The consequent odds risk ratio of developing Parkinson’s disease was calculated to be 33.8 [95% confidence interval (CI), 13.3–86.1] and for amyotrophic lateral sclerosis was 35.2 (95% CI, 13.0–85.1). Conclusions The possible involvement of the enzyme responsible for this S-oxidation biotransformation reaction, phenylalanine hydroxylase, should be further investigated to elucidate its potential role in the mechanism(s) of toxicity in susceptible individuals displaying these diseases. The “Janus hypothesis,” possibly explaining why phenylalanine hydroxylase is a biomarker of neurodegenerative disease susceptibility, together with the general theme that this concept may apply to many other hitherto unsuspected enzyme systems, is presented.

May 30, 2019

Drug-drug interaction (DDI) assessments of ruxolitinib, a dual substrate of CYP3A4 and CYP2C9, using a verified physiologically based pharmacokinetic (PBPK) model to support regulatory submissions

Kenichi Umehara, Felix Huth, Yi Jin, Hilmar Schiller, Vassilios Aslanis, Tycho Heimbach, Handan He

Article number: 20180042

Abstract

Ruxolitinib is mainly metabolized by cytochrome P450 (CYP) enzymes CYP3A4 and CYP2C9 followed by minor contributions of other hepatic CYP enzymes in vitro . A physiologically based pharmacokinetic (PBPK) model was established to evaluate the changes in the ruxolitinib systemic exposures with co-administration of CYP3A4 and CYP2C9 perpetrators. The fractions metabolized in the liver via oxidation by CYP enzymes (fm,CYP3A4 = 0.75, fm,CYP2C9 = 0.19, and fm,CYPothers = 0.06) for an initial ruxolitinib model based on in vitro data were optimized (0.43, 0.56, and 0.01, respectively) using the observed exposure changes of ruxolitinib (10 mg) with co-administered ketoconazole (200 mg). The reduced amount of fm,CYP3A4 was distributed to fm,CYP2C9. For the initial ruxolitinib model with co-administration of ketoconazole, the area under the curve (AUC) increase of 2.60-fold was over-estimated compared with the respective observation (1.91-fold). With the optimized fm values, the predicted AUC ratio was 1.82. The estimated AUC ratios of ruxolitinib by co-administration of the moderate CYP3A4 inhibitor erythromycin (500 mg) and the strong CYP3A4 inducer rifampicin (600 mg) were within a 20% error compared with the clinically observed values. The PBPK modeling results may provide information on the labeling, i.e. supporting a dose reduction by half for co-administration of strong CYP3A4 inhibitors. Furthermore, an AUC increase of ruxolitinib in the absence or presence of the dual CYP3A4 and CYP2C9 inhibitor fluconazole (100–400 mg) was prospectively estimated to be 1.94- to 4.31-fold. Fluconazole simulation results were used as a basis for ruxolitinib dose adjustment when co-administering perpetrator drugs. A ruxolitinib PBPK model with optimized fm,CYP3A4 and fm,CYP2C9 was established to evaluate victim DDI risks. The previous minimal PBPK model was supported by the FDA for the dose reduction strategy, halving the dose with the concomitant use of strong CYP3A4 inhibitors and dual inhibitors on CYP2C9 and CYP3A4, such as fluconazole at ≤200 mg. Fluconazole simulation results were used as supportive evidence in discussions with the FDA and EMA about ruxolitinib dose adjustment when co-administering perpetrator drugs. Thus, this study demonstrated that PBPK modeling can support characterizing DDI liabilities to inform the drug label and might help reduce the number of clinical DDI studies by simulations of untested scenarios, when a robust PBPK model is established.

June 29, 2019

Enhanced oral bioavailability of linagliptin by the influence of gallic acid and ellagic acid in male Wistar albino rats: involvement of p-glycoprotein inhibition

Munthaj Shaik, Swaroopa Rani Vanapatla

Article number: 20180020

Abstract

Background Linagliptin is an antidiabetic drug used for the treatment of type-2 diabetes. The oral bioavailability of linagliptin is low (29.5%) due to its first pass metabolism in the intestine and liver. Gallic acid and ellagic acid are natural polyphenols which are widely distributed in fruits and medicinal plants. Gallic acid and ellagic acid have been reported to inhibit p-glycoprotein (p-gp) and enhance the bioavailability of p-gp substrate drugs. Hence, the purpose of the study was to evaluate the effect of gallic acid and ellagic acid on intestinal transport and bioavailability of linagliptin, a p-gp substrate in diabetic rats. Methods The intestinal transport of linagliptin was assessed by conducting an in situ single-pass intestinal perfusion study. The oral pharmacokinetics was evaluated by conducting oral bioavailability study in diabetic rats. Results After pretreatment with gallic acid and ellagic acid, no significant change in effective permeability of linagliptin was observed at the ileum part of the rat intestine. A significant improvement in the peak serum concentration (C max ) and area under the serum concentration time profile (AUC), AUMC, AUC total and decrease in clearance were observed in rats pretreated with gallic acid and ellagic acid. Conclusions This study demonstrates that gallic acid and ellagic acids increase the bioavailability of oral linagliptin in rats due to the inhibition of p-gp. These animal data need to be confirmed in a clinical setting to determine whether linagliptin dosing should be adjusted when given concomitantly with these phytochemicals or gallic acid/ellagic acid-containing dietary supplements.

June 6, 2019

Treatment of adult lead poisoning with D-penicillamine

Maryam Paeezi, Nasim Zamani, Hossein Hassanian-Moghaddam, Shahin Shadnia, Naghmeh Zamani, Vahid Chaleshi, Amir Ali Mafi

Article number: 20190003

Abstract

Background The aim of the current study was to evaluate the efficacy of D-penicillamine in the treatment of lead poisoning mainly in the outpatient setting. Methods In a case series study performed during the recent epidemic of lead poisoning in Iran, lead-poisoned patients referring to our outpatient clinic were treated with 250-mg D-penicillamine capsules administered every 6 h for 5 or 10 days based on availability of the medication. They were recommended to re-check blood lead level (BLL) 4 weeks after cessation of the treatment and refer to our clinic again. Results In 63 patients with lead poisoning but without signs and symptoms of lead encephalopathy, median BLL was 106 [84, 131] μg/dL on presentation, which declined to a mean of 52.6 ± 28.8 μg/dL after a median treatment period of 7 [5, 10] days (p < 0.001). There was no statistically significant difference between the 5- and 10-day treatment protocols regarding complications and recovery. Treatment had resulted in a median decrease of 54 μg/dL [33, 90] (range: −20 to 231 μg/dL) in the patients’ BLLs (33.9% declined in BLL measurements; range: −29.69% to 99.06%). Conclusions D-penicillamine may be an acceptable substitute treatment in adult lead poisoning. Although our sample size was limited, we could not detect any serious adverse effects in our cases showing that D-penicillamine resulted in acceptable recovery rates. This may be helpful especially in epidemics with limitations in antidote access.

May 30, 2019

The effect of curcumin with piperine supplementation on pro-oxidant and antioxidant balance in patients with non-alcoholic fatty liver disease: a randomized, double-blind, placebo-controlled trial

Seyed Reza Mirhafez, Azam Rezaei Farimani, Ali Gholami, Elham Hooshmand, Shima Tavallaie, B. Fatemeh Nobakht M. Gh

Article number: 20180040

Abstract

Background The main causes of the progression of non-alcoholic fatty liver disease (NAFLD) are enhanced levels of reactive oxygen species and lipid peroxidation products. Therefore, the usage of antioxidant agents for the prevention and remedy of this disorder was recommended. Curcumin is proposed to treat NAFLD due to its high antioxidative activity. The aim of this study was to examine the effect of curcumin with piperine supplementation on oxidative stress in subjects with NAFLD. Methods In this double-blind, placebo-controlled trial, 55 subjects were randomly divided into two groups (curcumin with piperine and placebo). The participants received administrations of curcumin (500 mg) in combination with piperine (5 mg) and placebo daily for 8 weeks. Oxidative stress was assessed by measuring serum pro-oxidant and antioxidant balance (PAB) assay before and after the intervention. Results The serum PAB values did not significantly change between the treatment group vs. age and gender-matched placebo group after 8 weeks of supplementation. Also, curcumin in combination with piperine did not show a significant decrease (p = 0.06) in PAB levels compared to baseline. Conclusions The present study demonstrated that a dose of curcumin, co-supplied with piperine might be less than a dose in which curcumin can significantly decrease PAB values in these patients.

Case Report

May 30, 2019

Next-generation sequencing reveals mutations in RB1, CDK4 and TP53 that may promote chemo-resistance to palbociclib in ovarian cancer

Said El Shamieh, Fatima Saleh, Shafka Assaad, Fadi Farhat

Article number: 20180027

Abstract

Because of the profound heterogeneity of ovarian cancer at the clinical, cellular and molecular levels, herein we discuss the molecular findings at the protein and genetic levels seen in our patient. Immunohistochemistry showed a complete loss of phosphatase and tensin homolog, this observation was the reason behind prescribing the CDK4/6 inhibitor palbociclib. However, there was no response to treatment. Next-generation sequencing analysis was performed showing a nonsense mutation, p.R552X in retinoblastoma 1 ( RB1 ). This nonsense variation will possibly lead to a truncated protein lacking the domain responsible for interaction with E2F, an event that will induce cell cycle progression and, thus, be responsible for the chemo-resistance to palbociclib.

About this journal

Objective
Drug Metabolism and Personalized Therapy (DMPT) is the official journal of the European Society of Pharmacogenomics and Personalised Therapy (ESPT). DMPT provides up-to-date research articles, reviews and opinion papers in the wide field of drug metabolism research, covering established, new and potential drugs, environmentally toxic chemicals, the mechanisms by which drugs may interact with each other and with biological systems, and the pharmacological and toxicological consequences of these interactions and drug metabolism and excretion.
DMPT is an international scientific single-blind peer-review journal, which is issued quarterly with 8-10 articles per issue. The Journal publishes only English-language articles.

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Topics

drug metabolizing enzymes
pharmacogenetics and pharmacogenomics
biochemical pharmacology
molecular pathology
clinical pharmacology
pharmacokinetics and drug-drug interactions
immunopharmacology
neuropsychopharmacology

Article formats
Research Articles, Reviews and Mini Reviews, Opinion Papers, Short Communications, letters to the Editor, Case Reports, Editorials