European Journal of Drug Metabolism and Pharmacokinetics (EUR J DRUG METAB PH)

Publisher: Springer Verlag

Journal description

The European Journal of Drug Metabolism and Pharmacokinetics addresses all aspects of pre-clinical and clinical pharmacokinetics, including drug disposition, drug metabolism, drug transport, drug interactions, bioavailability and biopharmacy. The journal welcomes publications in the field of pharmacokinetic modeling. Analytical methods validation and bioequivalence studies will not be considered for publication. The journal publishes original articles, short preliminary communications, review articles on special topics, and conference proceedings. The European Journal of Drug Metabolism and Pharmacokinetics publishes four issues a year.

Current impact factor: 1.56

Impact Factor Rankings

2015 Impact Factor Available summer 2016
2014 Impact Factor 1.563
2013 Impact Factor 1.312
2012 Impact Factor 0.944
2011 Impact Factor 0.356
2010 Impact Factor 0.353
2009 Impact Factor 0.677
2008 Impact Factor 0.738
2007 Impact Factor 0.565
2006 Impact Factor 0.479
2005 Impact Factor 0.585
2004 Impact Factor 0.447
2003 Impact Factor 0.474
2002 Impact Factor 0.329
2001 Impact Factor 0.392
2000 Impact Factor 0.488
1999 Impact Factor 0.419
1998 Impact Factor 0.556
1997 Impact Factor 0.567
1996 Impact Factor 0.506
1995 Impact Factor 0.604
1994 Impact Factor 0.489
1993 Impact Factor 0.37
1992 Impact Factor 0.723

Impact factor over time

Impact factor

Additional details

5-year impact 1.25
Cited half-life >10.0
Immediacy index 0.38
Eigenfactor 0.00
Article influence 0.30
Website European Journal of Drug Metabolism and Pharmacokinetics website
Other titles European journal of drug metabolism and pharmacokinetics
ISSN 0378-7966
OCLC 2181264
Material type Periodical
Document type Journal / Magazine / Newspaper

Publisher details

Springer Verlag

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  • Classification

Publications in this journal

  • [Show abstract] [Hide abstract]
    ABSTRACT: Background and objectives: β-Lapachone (βLAP) is a promising, poorly soluble, antitumoral drug. βLAP combination with cyclodextrins (CDs) improves its solubility and dissolution but there is not enough information about the impact of cyclodextrins on βLAP intestinal permeability. The objectives of this work were to characterize βLAP intestinal permeability and to elucidate cyclodextrins effect on the dissolution properties and on the intestinal permeability. The final goal was to evaluate CDs influence on the oral absorption of βLAP. Methods: Binary systems (physical mixtures and inclusion complexes) including βLAP and CDs (β-cyclodextrin: βCD, random-methyl-β-cyclodextrin: RMβCD and sulfobutylether-β-cyclodextrin: SBEβCD) have been prepared and analysed by differential scanning calorimetry. βLAP (and its combinations with CDs) absorption rate coefficients and effective permeability values have been determined in vitro in MDCK or MDCK-Mdr1 monolayers and in situ in rat by a closed loop perfusion technique. Results: DSC results confirmed the formation of the inclusion complexes. βLAP-CDs inclusion complexes improve drug solubility and dissolution rate in comparison with physical mixtures. βLAP presented a high permeability value which can provide complete oral absorption. Its oral absorption is limited by its low solubility and dissolution rate. Cyclodextrin (both as physical mixtures and inclusion complexes) showed a positive effect on the intestinal permeability of βLAP. Complexation with CDs does not reduce βLAP intestinal permeability in spite of the potential negative effect of the reduction in free fraction of the drug. Conclusions: The use of RMβCD or SBEβCD inclusion complexes could benefit βLAP oral absorption by enhancing its solubility, dissolution rate and permeability.
    European Journal of Drug Metabolism and Pharmacokinetics 11/2015; DOI:10.1007/s13318-015-0310-5
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    ABSTRACT: Diabetes mellitus is becoming an increasingly prevalent disease that concerns patients and healthcare professionals worldwide. Among many anti-diabetic agents in clinical uses, numerous reports are available on their altered pharmacokinetics because of changes in the expression of drug transporters and metabolic enzymes under diabetic states. These changes may affect the safety and efficacy of therapeutic agents and/or drug-drug interaction with co-administered agents. Therefore, the changes in transporter expression should be identified, and the underlying mechanisms should be clarified. This review summarizes the progress of recent studies on the alterations in important uptake and efflux transporters in liver of diabetic animals and their regulatory pathways.
    European Journal of Drug Metabolism and Pharmacokinetics 11/2015; DOI:10.1007/s13318-015-0306-1
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    ABSTRACT: Background and objectives: Curcumin is the major bioactive component of turmeric, but has poor oral bioavailability that limits its clinical applications. To improve the in vitro solubility and alkaline stability, we developed a prodrug of curcumin by succinylation to obtain curcumin diethyl disuccinate, with the goal of improving the oral bioavailability of curcumin. Methods: The in vivo pharmacokinetic profile of curcumin diethyl disuccinate was compared with that of curcumin in male Wistar rats. Doses of curcumin 20 mg/kg intravenous or 40 mg/kg oral were used as standard regimens for comparison with the prodrug at equivalent doses in healthy adult rats. Blood, tissues, urine, and faeces were collected from time zero to 48 h after dosing to determine the prodrug level, curcumin level and a major metabolite by liquid chromatography-tandem spectrometry. Results: The absolute oral bioavailability of curcumin diethyl disuccinate was not significantly improved compared with curcumin, with both compounds having oral bioavailability of curcumin less than 1 %. The major metabolic pathway of the prodrug was rapid hydrolysis to obtain curcumin, followed by glucuronidation. Interestingly, curcumin diethyl disuccinate gave superior tissue distribution with higher tissue to plasma ratio of curcumin and curcumin glucuronide in several organs after intravenous dosing at 1 and 4 h. The primary elimination route of curcumin glucuronide occurred via biliary and faecal excretion, with evidence of an entry into the enterohepatic circulation. Conclusion: Curcumin diethyl disuccinate did not significantly improve the oral bioavailability of curcumin due to first pass metabolism in the gastrointestinal tract. Further studies on reduction of first pass metabolism are required to optimise delivery of curcumin using a prodrug approach.
    European Journal of Drug Metabolism and Pharmacokinetics 11/2015; DOI:10.1007/s13318-015-0308-z
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    ABSTRACT: Background and objectives: Glycopyrronium is a once-daily long-acting muscarinic antagonist for the maintenance treatment of patients with chronic obstructive pulmonary disease. This study assessed the pharmacokinetics of inhaled glycopyrronium 50 µg once-daily for 14 days in healthy Chinese subjects. Methods: In this open-label study, 12 Chinese healthy subjects (six males and six females; mean age 23.1 years [range 18-26 years]) were enrolled and completed the study. Glycopyrronium in plasma was determined using validated liquid chromatography-mass spectrometry method with a lower limit of quantification of 1.5 pg/mL. Plasma pharmacokinetic parameters were determined on Day 1 after first dose and on Day 14 (steady state) after last dose using non-compartmental analysis. Trough pharmacokinetic samples (Days 5, 7, 10 and 12) were collected. Safety was also assessed. Results: Glycopyrronium was rapidly absorbed into the systemic circulation after inhalation and its plasma concentrations decreased rapidly thereafter. Median time to reach maximum concentration (T max) was reached within 5 min after inhalation on both Days 1 and 14. Accumulation in the systemic exposure to glycopyrronium was observed from the time of first dose administration on Day 1 up to Day 14 and the observed accumulation ratio (R acc) values of area under the plasma drug concentration-time curve [AUC] from time 0 to 24 h post-dose (AUC0-24h) and maximum plasma drug concentration (C max) (Day 14/Day 1) were 2.77 and 1.59, respectively. The elimination half-life (T 1/2) was not reported. Mean effective half-life (T 1/2,acc) was 37.7 h. Pharmacokinetic steady state was reached after 5 days of daily dosing. One subject experienced dry mouth; otherwise glycopyrronium was well tolerated. Conclusions: Comparison of systemic exposure to glycopyrronium in Chinese versus the non-Chinese population did not indicate clinically relevant ethnic differences. Multiple inhaled doses of glycopyrronium were safe and well tolerated.
    European Journal of Drug Metabolism and Pharmacokinetics 10/2015; DOI:10.1007/s13318-015-0300-7
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    ABSTRACT: Human serum albumin (HSA) is the most frequent protein in blood plasma. Albumin transports various compounds, preserves osmotic pressure, and buffers pH. A unique feature of albumin is its ability to bind drugs and other bioactive molecules. However, it is important to consider binary and ternary systems of two pharmaceuticals to estimate the effect of the first drug on the second one and physicochemical properties. Different techniques including time-resolved, second-derivative and anisotropy fluorescence spectroscopy, resonance light scattering (RLS), critical induced aggregation concentration (C CIAC), particle size, zeta potential and stability analysis were employed in this assessment to elucidate the binding behavior of Amlodipine and Aspirin to HSA. Moreover, isothermal titration calorimetric techniques were performed and the QSAR properties were applied to analyze the hydration energy and log P. Multiple sequence alignments were also used to predict the structure and biological characteristics of the HSA binding site. Time-resolved fluorescence spectroscopy showed interaction of both drugs to HSA based on a static quenching mechanism. Subsequently, second-derivative fluorescence spectroscopy presented different values of parameter H in binary and ternary systems, which were suggested that tryptophan was in a more polar environment in the ternary system than in a binary system. Moreover, the polydispersity index and results from mean number measurements revealed that the presence of the second drug caused a decrease in the stability of systems and increased the heterogeneity of complex. It is also, observed that the gradual addition of HSA has led to a marked increase in fluorescence anisotropy (r) of Amlodipine and Aspirin which can be suggested that the drugs were located in a restricted environment of the protein as confirmed by Red Edge Excitation Shift (REES) studies. The isothermal titration calorimetric technique demonstrated that the interaction of the drugs with HSA was an enthalpically-driven process. The present experiment showed that the binding of Amlodipine and Aspirin to HSA induced a conformational change of HSA. It was also identified that the protein binding of the first drug could be affected by the second drug. Such results can be of great use for understanding the pharmacokinetic and pharmacodynamic mechanisms of drugs.
    European Journal of Drug Metabolism and Pharmacokinetics 09/2015; DOI:10.1007/s13318-015-0297-y
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    ABSTRACT: Herbal medicines are currently in high demand, and their popularity is steadily increasing. Because of their perceived effectiveness, fewer side effects and relatively low cost, they are being used for the management of numerous medical conditions. However, they are capable of affecting the pharmacokinetics and pharmacodynamics of coadministered conventional drugs. These interactions are particularly of clinically relevance when metabolizing enzymes and xenobiotic transporters, which are responsible for the fate of many drugs, are induced or inhibited, sometimes resulting in unexpected outcomes. This article discusses the general use of herbal medicines in the management of several ailments, their concurrent use with conventional therapy, mechanisms underlying herb-drug interactions (HDIs) as well as the drawbacks of herbal remedy use. The authors also suggest means of surveillance and safety monitoring of herbal medicines. Contrary to popular belief that "herbal medicines are totally safe," we are of the view that they are capable of causing significant toxic effects and altered pharmaceutical outcomes when coadministered with conventional medicines. Due to the paucity of information as well as sometimes conflicting reports on HDIs, much more research in this field is needed. The authors further suggest the need to standardize and better regulate herbal medicines in order to ensure their safety and efficacy when used alone or in combination with conventional drugs.
    European Journal of Drug Metabolism and Pharmacokinetics 08/2015; DOI:10.1007/s13318-015-0296-z
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    ABSTRACT: Rufinamide is a triazole derivative that is structurally unrelated to currently marketed antiepileptic medications for add-on treatment of seizures in the setting of Lennox-Gastaut syndrome in patients from the age of 4 years. The purpose of this study was to determine the pharmacokinetic and safety profile of single and multiple doses of rufinamide in healthy Chinese subjects. The effects of food and gender on the pharmacokinetic properties of rufinamide were also evaluated. In the single-dose study, volunteers were randomly assigned to 4 dose groups and received a single dose of 200, 400, 800, 1200 mg rufinamide tablets under fasting condition. Ten subjects in the 200-mg dose group were randomly assigned to either a high-fat or non-high-fat breakfast group in each study period. The drug administration was separated by a washout period of 7 calendar days. In the multiple-dose study, 10 subjects were administered on an empty stomach rufinamide 200 mg twice daily for 6 consecutive days. Liquid chromatography tandem mass spectrometry (LC-MS/MS) method was applied to determine plasma concentration of rufinamide. Pharmacokinetic parameters, including the maximum plasma concentration (C max), the time to peak concentration (t max), the area under the plasma concentration versus time curve from time 0 to the last measurable concentration (AUC0-t ) and from time 0 to infinity (AUC0-∞), terminal elimination half-life (t 1/2), apparent volume of distribution (V d), apparent clearance (CL), average residence time (MRT), area under the plasma concentration versus time curve from time 0 to the last measurable concentration at steady state (AUCss), peak concentration (C max,ss) and trough level concentration (C min,ss) at steady state were calculated using non-compartmental models. Tolerability was assessed based on investigator inquiries, spontaneous reports and clinical evaluations. Rufinamide displayed a dose-dependent, but sub-proportional increase in exposure following single-dose and repeated dose administration. After administration of single dose of 200, 400, 800 and 1200 mg, without food, the rufinamide mean C max (standard deviation, SD) was 1806.5 (526.4), 2490 (564.8), 3719 (976.1) and 4166 (1187.1) μg/L, respectively. Mean AUC0-t (SD) was 34,571 (9484), 56,246 (18,077), 89,022 (23,379) and 107,316 (34,766) μg·h/L, respectively. While in fed condition at the dosage of 200 mg, mean C max (SD) and mean AUC0-t (SD) were 2363 (582) μg/L and 40,593 (10,516) μg·h/L, respectively. After administration of multiple doses, arithmetic mean (SD) values of C max and AUC0-t were 3566 (873) μg/L and 62,803 (19,873) μg·h/L, respectively. The steady state was achieved by day 3 of multiple dosing after 2 daily doses (twice a day), the corresponding accumulation factor (AUCss/AUC0-t) was 0.9057. Although there were no substantial effects on exposure resulting from gender differences, a notable food effect was observed, with AUC and C max increased by 17.4 and 30.8 %, respectively. Single- and multiple-dose phases were generally safe and well tolerated. Overall, 15 % (6/40) of subjects experienced a mild indisposition with no serious adverse events. On single and multiple dosing, rufinamide exhibited nonlinear pharmacokinetics and was well tolerated in healthy Chinese subjects.
    European Journal of Drug Metabolism and Pharmacokinetics 08/2015; DOI:10.1007/s13318-015-0291-4
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    ABSTRACT: MTBH, a novel hesperetin derivative, possesses in vivo hepatoprotective effects against carbon tetrachloride (CCl4)-induced acute liver injury in Institute of Cancer Research (ICR) mice. This study investigated the pharmacokinetics and tissue distribution of MTBH and its conjugated metabolites in rats after a single dose of MTBH. Male Sprague-Dawley (SD) rats were orally administered (25, 50, 100 mg/kg) or intravenously administered (25 mg/kg) MTBH and blood samples were withdrawn at specific times. Moreover, after a single oral dose of MTBH (200 mg/kg), tissues (heart, liver, spleen, lung, kidney, stomach, intestine, brain and muscle) were collected at scheduled time points. The concentration of MTBH in plasma and tissues was assayed by HPLC before and after hydrolysis with β-glucuronidase or sulfatase. The glucuronides/sulfates were extensively present in the plasma, moreover, the free form was detectable in the plasma, but in a small amount equivalent to nearly 0.85-1.46 % of the amount of glucuronides/sulfates, the absolute bioavailability of MTBH was approximately 31.27 %. In tissues, the free form appeared in all tissues examined, with trace amount in brain and muscle, and considerable concentration in stomach and lung. Glucuronides/sulfates were the major forms in intestine, kidney and liver, whereas not detectable in heart, brain and muscle. The liver and intestine were found likely to accumulate MTBH at a high concentration among all tissues. The free form of MTBH was present in the circulation and all assayed organs, whereas its glucuronides/sulfates were the major forms in plasma and intestine, kidney and liver after a single dose.
    European Journal of Drug Metabolism and Pharmacokinetics 08/2015; DOI:10.1007/s13318-015-0293-2
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    ABSTRACT: Imatinib mesylate is presently the first-line treatment for chronic myeloid leukemia (CML). The aim of this study was to investigate the absorption and distribution kinetics of imatinib in healthy Iranian volunteers using nonlinear mixed effects modeling (NLMEM) to assess the overall, intra- and inter-subject variabilities in pharmacokinetic parameters after oral administration. This analysis was based on data from 24 healthy subjects who participated in a bioequivalence study after administering a single dose of 200 mg of each formulation. Imatinib concentrations were quantified using a validated liquid chromatography method. To simultaneously describe the imatinib pharmacokinetic profiles obtained with both formulations, a population pharmacokinetic model was applied to data using SAEM algorithm implemented in MONOLIX, whilst simulations were used by numerical solving of ordinary differential equations to calculate secondary parameters in individuals for bioequivalence studies. According to goodness-of-fit criteria, a two-compartment open model with sequential zero- then first-order absorption and first-order elimination was used as the structural pharmacokinetic model. Inter-individual variability (IIV) was considered for all parameters. Typical population estimates (% IIV) were fraction of the drug absorbed with a zero-order kinetic (Fr) of 0.153 (47.9 %) in period (Tk0) of 0.714 h (47.4 %), first-order absorption rate constant (k a) of 0.94 h(-1)(31.2 %), oral clearance of 19 L/h (27.9 %), central volume of distribution (V c/F) of 139 L (21.5 %), apparent peripheral volume of distribution (V p/F) of 130 L (29.7 %) and the apparent inter-compartment clearance (Q/F) of 29.6 L/h (41.8 %). Body mass index (BMI) was the only covariate found to significantly affect V p /F. The coefficient of variation for intra-individual plasma exposure (AUC0-∞) was 27.8 %. Analyses using NLMEM for imatinib exhibited absorption complexities such as two input rates and medium to high intra-individual variability in drug exposure.
    European Journal of Drug Metabolism and Pharmacokinetics 07/2015; DOI:10.1007/s13318-015-0292-3
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    ABSTRACT: The purpose of the current study was to investigate the effect of the dosing time on the pharmacokinetics of erlotinib and the circadian rhythms of the metabolism enzymes in tumor-bearing mice. Female C57BL mice were randomly assigned to six groups. Erlotinib was orally administrated to the mice in each group at six different times of day. The plasma concentration of erlotinib was determined through a high-performance liquid-chromatographic assay, and the total mRNA was extracted from liver tissues to determine the expression of the mRNA of the related drug metabolism enzymes by qRT-PCR. The results indicated that AUC0-24 h and MRT0-24 h were the lowest in the 20:00 group (P < 0.01). T max of the 13 HALO (hour after light onset), 17 HALO and 21 HALO groups was higher than that of the 1 HALO and 5 HALO groups (P < 0.01). CL of the light-phase groups was lower than that of the dark-phase groups (P < 0.01). The peak value of C max appeared in the 5 HALO group (P < 0.01). The mRNA levels of Cyp3a11, Cyp3a13 and Cyp1a2 were generally higher during the afternoon and the dark phase. Circadian rhythm plays a critical role in the pharmacokinetics of erlotinib in mice, and the mechanisms may be attributed to gene expression rhythms of drug-metabolizing enzymes in liver tissues.
    European Journal of Drug Metabolism and Pharmacokinetics 07/2015; DOI:10.1007/s13318-015-0284-3
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    ABSTRACT: Propofol is the most commonly used hypnotic worldwide, but its effective dose varies greatly between individuals. The present study sought to investigate the relationship between the c.516G>T polymorphism in the CYP2B6 (cytochrome P450 2B6) gene and the required propofol dose. One hundred and eight patients treated with propofol were recruited, and environmental, clinical and surgical data were collected. Genotyping for the c.516G>T polymorphism was performed by real-time PCR. Multiple linear regression analysis was performed to estimate the predictive variables of the total propofol dose. For patients under general anaesthesia, the predictive variables of the total propofol dose were surgery duration (partial R (2) = 19.9 %), age (partial R (2) = 10.5 %), weight (partial R (2) = 10.1 %) and presence of the T allele (partial R (2) = 6.8 %). From the estimated coefficient of regression values, the surgery duration and weight were the factors that increased the propofol dose, while age and presence of the T allele decreased the total dose of the drug needed. The total propofol doses based on the GG or GT/TT genotypes were 151.5 ± 64.2 mg and 129.3 ± 44.6 mg, respectively (p = 0.043). Our results indicate that 34 % of the variance in the required propofol dose may be explained by these factors and that CYP2B6 c.516G>T polymorphism, which decreases the metabolism of the drug, accounts for approximately 7 % of the drug dosage. Our results show the possible influence of CYP2B6 c.516G>T genetic variant on propofol dose in patients under general anaesthesia.
    European Journal of Drug Metabolism and Pharmacokinetics 07/2015; DOI:10.1007/s13318-015-0289-y
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    ABSTRACT: Isocorynoxeine (IC), a major alkaloid found in Uncaria rhynchophylla, exhibits wide beneficial effects on the cardiovascular and cardiocerebral vascular systems. Its metabolic pathway, however, has not been well studied yet. In this study, an ultra-high-performance liquid chromatography/quadrupole time-of-flight mass spectrometry (U-HPLC/Q-TOFMS) method was developed to investigate IC metabolism in plasma, urine and bile in rats given IC orally at 40 mg/kg. Nine male Wistar rats were given IC 40 mg/kg orally. Blood, urine and bile samples were collected at pre-specified times to measure the concentration of IC. A total of 35 metabolites were tentatively identified by the co-chromatography of biosamples and comparison of the retention time, characteristic molecular ions and fragment ions with those of the authentic standards or tentatively identified by MS/MS determination along with MassFragment software. Among them, 18, 33 and 18 metabolites were found in plasma, urine and bile samples, respectively. The relative percentage area of each metabolite was also determined to better understand the major metabolic pathways of IC in rats. The result indicates that IC undergoes extensive metabolism in vivo, mainly including hydrolysis, oxidation, isomerization, demethylation, epoxidation, reduction, glucuronidation, hydroxylation and N-oxidation, which is helpful for the further pharmacokinetic study of IC in vivo.
    European Journal of Drug Metabolism and Pharmacokinetics 06/2015; DOI:10.1007/s13318-015-0287-0
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    ABSTRACT: Nalfurafine hydrochloride (TRK-820), which exhibits strong κ-opioid agonistic activity, has an antipruritic effect on uremic pruritus. The permeability of nalfurafine across human P-glycoprotein (P-gp)-expressing LLC-PK1 cells was investigated to evaluate drug-drug interactions (DDI) involving the P-gp efflux transporter of nalfurafine. Furthermore, we assessed the ratio of brain/plasma concentrations (K p) as an indicator to investigate the changes in the blood-brain barrier (BBB) transport through P-gp when digoxin or verapamil was concomitantly administered with nalfurafine in mice. All samples were analyzed by liquid chromatography-tandem mass spectrometry or a liquid scintillation counter. The cleared volume ratio (cleared volume from basal to apical/cleared volume from apical to basal) of nalfurafine in P-gp-expressing cells was higher than that in the control cells; however, no concentration-dependent decrease in the cleared volume ratio of digoxin was observed in the presence of nalfurafine. The K p value in mice showed similar profiles to those observed with nalfurafine alone and when co-administered with digoxin or verapamil. From these results, nalfurafine was found to be a substrate for P-gp, but had no inhibitory effect on P-gp-mediated transport. Furthermore, it is unlikely that nalfurafine transport via the BBB is affected by P-gp substrates in humans.
    European Journal of Drug Metabolism and Pharmacokinetics 06/2015; DOI:10.1007/s13318-015-0286-1