Special Issue "Pharmacokinetic Drug-Drug Interactions and Herb-Drug Interactions"

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Pharmacokinetics and Pharmacodynamics".

Deadline for manuscript submissions: closed (31 October 2020).

Special Issue Editors

Prof. Dr. Im-Sook Song
E-Mail Website
Guest Editor
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 41566, Korea
Interests: pharmacokinetic drug–drug interaction; pharmacokinetic herb–drug interaction; drug-metabolizing enzymes and transporters; pharmacokinetic/pharmacodynamics in drug development; oral bioavailability
Special Issues and Collections in MDPI journals
Prof. Dr. Min-Koo Choi
E-Mail Website
Guest Editor
College of Pharmacy, Dankook University, Cheon-an 31116, Korea
Interests: Pharmacokinetic drug-drug interaction; Pharmacokinetic herb-drug interaction; Bioanalysis; Drug delivery system
Special Issues and Collections in MDPI journals

Special Issue Information

Dear Colleagues,

Due to the growing use of herbal medicine and easy of taking herbal medicine formulation with therapeutics drugs and with a trend of polypills, adverse drug reactions or drug/herb-drug interactions caused by co-administration of therapeutic drugs and herbal medicine have been rapidly growing. In USA, about 76% of the adult population consumed herbal supplements in 2017 and increased about 12% compared to 64% nine years ago. Moreover, about 25% of herbal supplemental users regularly take prescribed drugs, which increased the possibility of herb-drug interaction. The most frequently reported case of herb-drug interactions included the modulation of herbal medicine on drug metabolizing enzymes and transporters and the causative pharmacokinetic effect of co-administered therapeutic drugs that are substrate for drug metabolizing enzymes and transporters. In most cases, the pharmacokinetic principles and drug interaction issues for the concomitantly administered therapeutic drugs have been applied to the herbal medicines.

Therefore, this special issue has the aim of highlighting the pharmacokinetic drug-drug interactions and herb-drug interaction and their mechanistic understanding in relation to the drug metabolizing enzymes and drug transporters. For this, the bioanalytical method development for the measurement of pharmacological active component of concomitantly administered herbal medicines is also important.

Prof. Dr. Im-Sook Song
Prof. Dr. Min-Koo Choi
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceutics is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2200 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Pharmacokinetic drug-drug interaction
  • Pharmacokinetic herb-drug interaction
  • Drug metabolizing enzymes
  • Drug transporters
  • Bioanalysis of pharmacological active component of herbal medicines

Related Special Issue

Published Papers (17 papers)

Order results
Result details
Select all
Export citation of selected articles as:

Editorial

Jump to: Research, Review, Other

Open AccessEditorial
Pharmacokinetic Drug–Drug Interactions and Herb–Drug Interactions
Pharmaceutics 2021, 13(5), 610; https://doi.org/10.3390/pharmaceutics13050610 - 23 Apr 2021
Viewed by 214
Abstract
Due to the growing use of herbal supplementation—ease of taking herbal supplements with therapeutics drugs (i [...] Full article
(This article belongs to the Special Issue Pharmacokinetic Drug-Drug Interactions and Herb-Drug Interactions)

Research

Jump to: Editorial, Review, Other

Open AccessArticle
Prevalence and Clinical Significance of Drug–Drug and Drug–Dietary Supplement Interactions among Patients Admitted for Cardiothoracic Surgery in Greece
Pharmaceutics 2021, 13(2), 239; https://doi.org/10.3390/pharmaceutics13020239 - 09 Feb 2021
Cited by 1 | Viewed by 618
Abstract
Background: Drug interactions represent a major issue in clinical settings, especially for critically ill patients such as those with cardiovascular disease (CVD) who require cardiothoracic surgery (CTS) and receive a high number of different medications. Methods: A cross-sectional study aimed at evaluating the [...] Read more.
Background: Drug interactions represent a major issue in clinical settings, especially for critically ill patients such as those with cardiovascular disease (CVD) who require cardiothoracic surgery (CTS) and receive a high number of different medications. Methods: A cross-sectional study aimed at evaluating the exposure and clinical significance of drug–drug (DDIs) and drug–dietary supplement interactions (DDSIs) in patients admitted for CTS in the University Hospital of Crete Greece. DDIs were evaluated regarding underlying pharmacological mechanisms upon admission, preoperation, postoperation, and discharge from CTS clinic. Additionally, upon admission, the use of dietary supplements (DSs) and if patients had informed their treating physician that they were using these were recorded with subsequent analysis of potential DDSIs with prescribed medications. Results: The study employed 76 patients who were admitted for CTS and accepted to participate. Overall, 166 unique DDIs were identified, with 32% of them being related to pharmacokinetic (PK) processes and the rest (68%) were related to possible alterations of pharmacodynamic (PD) action. CVD medications and drugs for central nervous system disorders were the most frequently interacting medications. In total, 12% of the identified DDIs were of serious clinical significance. The frequency of PK-DDIs was higher during admission and discharge, whereas PD-DDIs were mainly recorded during pre- and postoperation periods. Regarding DS usage, 60% of patients were using DSs and perceived them as safe, and the majority had not informed their treating physician of this or sought out medical advice. Analysis of medical records showed 30 potential combinations with prescribed medications that could lead in DDSIs due to modulation of PK or PD processes, and grapefruit juice consumption was involved in 38% of them. Conclusions: An increased burden of DDIs and DDSIs was identified mostly upon admission for patients in CTS clinics in Greece. Healthcare providers, especially prescribing physicians in Greece, should always take into consideration the possibility of DDIs and the likely use of DS products by patients to promote their well-being; this should only be undertaken after receiving medical advice and an evidenced-based evaluation. Full article
(This article belongs to the Special Issue Pharmacokinetic Drug-Drug Interactions and Herb-Drug Interactions)
Show Figures

Graphical abstract

Open AccessArticle
Clinical Evaluation of Acetaminophen–Galgeuntang Interaction Based on Population Approaches
Pharmaceutics 2020, 12(12), 1182; https://doi.org/10.3390/pharmaceutics12121182 - 04 Dec 2020
Cited by 1 | Viewed by 632
Abstract
Galgeuntang (GGT), a traditional herbal medicine, is widely co-administered with acetaminophen (AAP) for treatment of the common cold, but this combination has not been the subject of investigation. Therefore, we investigated the herb–drug interaction between GGT and AAP by population pharmacokinetics (PKs) modeling [...] Read more.
Galgeuntang (GGT), a traditional herbal medicine, is widely co-administered with acetaminophen (AAP) for treatment of the common cold, but this combination has not been the subject of investigation. Therefore, we investigated the herb–drug interaction between GGT and AAP by population pharmacokinetics (PKs) modeling and simulation studies. To quantify PK parameters and identify drug interactions, an open label, three-treatment, three-period, one-sequence (AAP alone, GGT alone, and AAP and GGT in combination) clinical trial involving 12 male healthy volunteers was conducted. Ephedrine (EPD), the only GGT component detected, was identified using a one-compartment model. The PKs of AAP were described well by a one-compartment model and exhibited two-phase absorption (rapid followed by slow) and first-order elimination. The model showed that EPD significantly influenced the PKs of AAP. The simulation results showed that at an AAP dose of 1000 mg × 4 times daily, the area under the concentration versus time curve of AAP increased by 16.4% in the presence of GGT compared to AAP only. In conclusion, the PKs of AAP were affected by co-administration of GGT. Therefore, when AAP is combined with GGT, adverse effects related to overdose of AAP could be induced possibly. Full article
(This article belongs to the Special Issue Pharmacokinetic Drug-Drug Interactions and Herb-Drug Interactions)
Show Figures

Figure 1

Open AccessArticle
Differential Effects of 1α,25-Dihydroxyvitamin D3 on the Expressions and Functions of Hepatic CYP and UGT Enzymes and Its Pharmacokinetic Consequences In Vivo
Pharmaceutics 2020, 12(11), 1129; https://doi.org/10.3390/pharmaceutics12111129 - 23 Nov 2020
Cited by 1 | Viewed by 580
Abstract
The compound 1α,25-Dihydroxyvitamin D3 (1,25(OH)2D3) is the active form of vitamin D3 and a representative ligand of the vitamin D receptor (VDR). Previous studies have described the impacts of 1,25(OH)2D3 on a small number [...] Read more.
The compound 1α,25-Dihydroxyvitamin D3 (1,25(OH)2D3) is the active form of vitamin D3 and a representative ligand of the vitamin D receptor (VDR). Previous studies have described the impacts of 1,25(OH)2D3 on a small number of cytochrome P450 (CYP) and uridine diphosphate-glucuronyltransferase (UGT) enzymes, but comparatively little is known about interactions between several important CYP and UGT isoforms and 1,25(OH)2D3 in vitro and/or in vivo. Thus, we investigated the effects of 1,25(OH)2D3 on the gene and protein expressions and functional activities of selected CYPs and UGTs and their impacts on drug pharmacokinetics in rats. The mRNA/protein expressions of Cyp2b1 and Cyp2c11 were downregulated in rat liver by 1,25(OH)2D3. Consistently, the in vitro metabolic kinetics (Vmax and CLint) of BUP (bupropion; a Cyp2b1 substrate) and TOL (tolbutamide; a Cyp2c11 substrate) were significantly changed by 1,25(OH)2D3 treatment in liver microsomes, but the kinetics of acetaminophen (an Ugt1a6/1a7/1a8 substrate) remained unaffected, consistent with Western blotting data for Ugt1a6. In rat pharmacokinetic studies, the total body clearance (CL) and nonrenal clearance (CLNR) of BUP were significantly reduced by 1,25(OH)2D3, but unexpectedly, the total area under the plasma concentration versus time curve from time zero to infinity (AUC) of hydroxybupropion (HBUP) was increased probably due to a marked reduction in the renal clearance (CLR) of HBUP. Additionally, the AUC, CL, and CLNR for TOL and the AUC for 4-hydroxytolbutamide (HTOL) were unaffected by 1,25(OH)2D3 in vivo. Discrepancies between observed in vitro metabolic activity and in vivo pharmacokinetics of TOL were possibly due to a greater apparent distribution volume at the steady-state (Vss) and lower plasma protein binding in 1,25(OH)2D3-treated rats. Our results suggest possible drug-drug and drug-nutrient interactions and provide additional information concerning safe drug combinations and dosing regimens for patients taking VDR ligand drugs including 1,25(OH)2D3. Full article
(This article belongs to the Special Issue Pharmacokinetic Drug-Drug Interactions and Herb-Drug Interactions)
Show Figures

Figure 1

Open AccessArticle
The Development and Validation of a Novel “Dual Cocktail” Probe for Cytochrome P450s and Transporter Functions to Evaluate Pharmacokinetic Drug-Drug and Herb-Drug Interactions
Pharmaceutics 2020, 12(10), 938; https://doi.org/10.3390/pharmaceutics12100938 - 30 Sep 2020
Cited by 2 | Viewed by 738
Abstract
This study was designed to develop and validate a 10 probe drug cocktail named “Dual Cocktail”, composed of caffeine (Cyp1a2 in rat and CYP1A2 in human, 1 mg/kg), diclofenac (Cyp2c11 in rat and CYP2C9 in human, 2 mg/kg), omeprazole (Cyp2c11 in rat and [...] Read more.
This study was designed to develop and validate a 10 probe drug cocktail named “Dual Cocktail”, composed of caffeine (Cyp1a2 in rat and CYP1A2 in human, 1 mg/kg), diclofenac (Cyp2c11 in rat and CYP2C9 in human, 2 mg/kg), omeprazole (Cyp2c11 in rat and CYP2C19 in human, 2 mg/kg), dextromethorphan (Cyp2d2 in rat and CYP2D6 in human, 10 mg/kg), nifedipine (Cyp3a1 in rat and CYP3A4 in human, 0.5 mg/kg), metformin (Oct1/2 in rat and OCT1/2 in human, 0.5 mg/kg), furosemide (Oat1/3 in rat and OAT1/3 in human, 0.1 mg/kg), valsartan (Oatp2 in rat and OATP1B1/1B3 in human, 0.2 mg/kg), digoxin (P-gp in rat and human, 2 mg/kg), and methotrexate (Mrp2 in rat and MRP2 in human, 0.5 mg/kg), for the evaluation of pharmacokinetic drug–drug and herb-drug interactions through the modulation of a representative panel of CYP enzymes or transporters in rats. To ensure no interaction among the ten probe substrates, we developed a 2-step evaluation protocol. In the first step, the pharmacokinetic properties of five individual CYP probe substrates and five individual transporter substrates were compared with the pharmacokinetics of five CYP cocktail or five transporters cocktails in two groups of randomly assigned rats. Next, a pharmacokinetic comparison was conducted between the CYP or transporter cocktail group and the dual cocktail group, respectively. None of the ten comparison groups was found to be statistically significant, indicating the CYP and transporter substrate sets or dual cocktail set could be concomitantly administered in rats. The “Dual Cocktail” was further validated by assessing the metabolism of nifedipine and omeprazole, which was significantly reduced by a single oral dose of ketoconazole (10 mg/kg); however, no changes were observed in the pharmacokinetic parameters of other probe substrates. Additionally, multiple oral doses of rifampin (20 mg/kg) reduced the plasma concentrations of nifedipine and digoxin, although not any of the other substrates. In conclusion, the dual cocktail can be used to characterize potential pharmacokinetic drug–drug interactions by simultaneously monitoring the activity of multiple CYP isoforms and transporters. Full article
(This article belongs to the Special Issue Pharmacokinetic Drug-Drug Interactions and Herb-Drug Interactions)
Show Figures

Graphical abstract

Open AccessArticle
Quasi-Irreversible Inhibition of CYP2D6 by Berberine
Pharmaceutics 2020, 12(10), 916; https://doi.org/10.3390/pharmaceutics12100916 - 24 Sep 2020
Cited by 1 | Viewed by 837
Abstract
In our previous study, Hwang-Ryun-Hae-Dok-Tang, which contains berberine (BBR) as a main active ingredient, inhibited cytochrome P450 (CYP) 2D6 in a quasi-irreversible manner. However, no information is available on the detailed mechanism of BBR-induced CYP2D6 inhibition. Thus, the present study aimed to characterize [...] Read more.
In our previous study, Hwang-Ryun-Hae-Dok-Tang, which contains berberine (BBR) as a main active ingredient, inhibited cytochrome P450 (CYP) 2D6 in a quasi-irreversible manner. However, no information is available on the detailed mechanism of BBR-induced CYP2D6 inhibition. Thus, the present study aimed to characterize the inhibition mode and kinetics of BBR and its analogues against CYP2D6 using pooled human liver microsomes (HLM). BBR exhibited selective quasi-irreversible inhibition of CYP2D6 with inactivation rate constant (kinact) of 0.025 min−1, inhibition constant (KI) of 4.29 µM, and kinact/KI of 5.83 mL/min/µmol. In pooled HLM, BBR was metabolized to thalifendine (TFD), demethyleneberberine (DMB), M1 (proposed as demethylene-TFD), and to a lesser extent berberrubine (BRB), showing moderate metabolic stability with a half-life of 35.4 min and a microsomal intrinsic clearance of 7.82 µL/min/mg protein. However, unlike BBR, those metabolites (i.e., TFD, DMB, and BRB) were neither selective nor potent inhibitors of CYP2D6, based on comparison of half-maximal inhibitory concentration (IC50). Notably, TFD, but not DMB, exhibited metabolism-dependent CYP2D6 inhibition as in the case of BBR, which suggests that methylenedioxybenzene moiety of BBR may play a critical role in the quasi-irreversible inhibition. Moreover, the metabolic clearance of nebivolol (β-blocker; CYP2D6 substrate) was reduced in the presence of BBR. The present results warrant further evaluation of BBR–drug interactions in clinical situations. Full article
(This article belongs to the Special Issue Pharmacokinetic Drug-Drug Interactions and Herb-Drug Interactions)
Show Figures

Graphical abstract

Open AccessArticle
Evaluation of the Pharmacokinetic Drug–Drug Interaction between Micronized Fenofibrate and Pitavastatin in Healthy Volunteers
Pharmaceutics 2020, 12(9), 869; https://doi.org/10.3390/pharmaceutics12090869 - 12 Sep 2020
Cited by 1 | Viewed by 760
Abstract
Dyslipidemia is a major risk factor for development of atherosclerosis and cardiovascular disease (CVD). Effective lipid-lowering therapies has led to CVD risk reduction. This study evaluated the possible pharmacokinetic interactions between fenofibrate, a peroxisome proliferators-activated receptors α agonist, and pitavastatin, a 3-hydoxy-3-methylglutaryl-coenzyme A [...] Read more.
Dyslipidemia is a major risk factor for development of atherosclerosis and cardiovascular disease (CVD). Effective lipid-lowering therapies has led to CVD risk reduction. This study evaluated the possible pharmacokinetic interactions between fenofibrate, a peroxisome proliferators-activated receptors α agonist, and pitavastatin, a 3-hydoxy-3-methylglutaryl-coenzyme A reductase inhibitor, in healthy Korean subjects. The study design was an open-label, randomized, multiple-dose, three-period, and six-sequence crossover study with a 10-day washout in 24 healthy volunteers. It had three treatments: 160 mg of micronized fenofibrate once daily for 5 days; 2 mg of pitavastatin once daily for 5 days; and 160 mg of micronized fenofibrate with 2 mg of pitavastatin for 5 days. Serial blood samples were collected at scheduled intervals for up to 48 h after the last dose in each period to determine the steady-state pharmacokinetics of both drugs. Plasma concentrations of fenofibric acid and pitavastatin were measured using a validated high-performance liquid chromatography with the tandem mass spectrometry method. A total of 24 subjects completed the study. Pitavastatin, when co-administered with micronized fenofibrate, had no effect on the Cmax,ss and AUCτ,ss of fenofibric acid. The Cmax,ss and AUCτ,ss of pitavastatin were increased by 36% and 12%, respectively, when co-administered with fenofibrate. Combined treatment with pitavastatin and micronized fenofibrate was generally well tolerated without serious adverse events. Our results demonstrated no clinically significant pharmacokinetic interactions between micronized fenofibrate and pitavastatin when 160 mg of micronized fenofibrate and 2 mg of pitavastatin are co-administered. The treatments were well tolerated during the study, with no serious adverse events. Full article
(This article belongs to the Special Issue Pharmacokinetic Drug-Drug Interactions and Herb-Drug Interactions)
Show Figures

Figure 1

Open AccessArticle
Influence of Probenecid on the Pharmacokinetics and Pharmacodynamics of Sorafenib
Pharmaceutics 2020, 12(9), 788; https://doi.org/10.3390/pharmaceutics12090788 - 20 Aug 2020
Cited by 2 | Viewed by 910
Abstract
Prior studies have demonstrated an organic anion transporter 6 (OAT6)-mediated accumulation of sorafenib in keratinocytes. The OAT6 inhibitor probenecid decreases sorafenib uptake in skin and might, therefore, decrease sorafenib-induced cutaneous adverse events. Here, the influence of probenecid on sorafenib pharmacokinetics and toxicity was [...] Read more.
Prior studies have demonstrated an organic anion transporter 6 (OAT6)-mediated accumulation of sorafenib in keratinocytes. The OAT6 inhibitor probenecid decreases sorafenib uptake in skin and might, therefore, decrease sorafenib-induced cutaneous adverse events. Here, the influence of probenecid on sorafenib pharmacokinetics and toxicity was investigated. Pharmacokinetic sampling was performed in 16 patients on steady-state sorafenib treatment at days 1 and 15 of the study. Patients received sorafenib (200–800 mg daily) in combination with probenecid (500 mg two times daily (b.i.d.)) on days 2–15. This study was designed to determine bioequivalence with geometric mean Area under the curve from zero to twelve hours (AUC0–12 h) as primary endpoint. During concomitant probenecid, sorafenib plasma AUC0–12 h decreased by 27% (90% CI: −38% to −14%; P < 0.01). Furthermore, peak and trough levels of sorafenib, as well as sorafenib concentrations in skin, decreased to a similar extent in the presence of probenecid. The metabolic ratio of sorafenib-glucuronide to parent drug increased (+29%) in the presence of probenecid. A decrease in systemic sorafenib concentrations during probenecid administration seems to have influenced cutaneous concentrations. Since sorafenib-glucuronide concentrations increased compared with sorafenib and sorafenib-N-oxide, probenecid may have interrupted enterohepatic circulation of sorafenib by inhibition of the organic anion transporting polypeptides 1B1 (OATP1B1). Sorafenib treatment with probenecid is, therefore, not bioequivalent to sorafenib monotherapy. A clear effect of probenecid on sorafenib toxicity could not be identified in this study. Full article
(This article belongs to the Special Issue Pharmacokinetic Drug-Drug Interactions and Herb-Drug Interactions)
Show Figures

Figure 1

Open AccessArticle
Extended Intake of Mulberry Leaf Extract Delayed Metformin Elimination via Inhibiting the Organic Cation Transporter 2
Pharmaceutics 2020, 12(1), 49; https://doi.org/10.3390/pharmaceutics12010049 - 07 Jan 2020
Cited by 5 | Viewed by 1020
Abstract
Diabetes mellitus (DM) has become a major health problem in most countries of the world. DM causes many complications, including hyperglycemia, diabetic ketoacidosis, and death. In Asia, mulberry has been used widely in the treatment of DM. Combination of drugs with herbal medicine [...] Read more.
Diabetes mellitus (DM) has become a major health problem in most countries of the world. DM causes many complications, including hyperglycemia, diabetic ketoacidosis, and death. In Asia, mulberry has been used widely in the treatment of DM. Combination of drugs with herbal medicine may reduce the unwanted side effects caused by drugs. In this study, the influence of extended mulberry leaves extract (MLE) intake on metformin (Met) was evaluated in terms of pharmacokinetics and pharmacodynamics in DM-induced rats. Three week-treatment of MLE alone produced the anti-hyperglycemic effect (around 24%) if compared to the control. Interestingly, Met administration after MLE treatment for 3 weeks enhanced about 49% of the anti-hyperglycemic effect of Met. In addition, the extended intake of MLE potentiated the anti-hyperglycemic effect of Met on various concentrations. This potentiated anti-hyperglycemic effect of Met appears to be due to the pharmacokinetic change of Met. In this study, 3 week-treatment of MLE reduced the elimination of Met in DM-induced rats. In addition, MLE reduced the human organic cation transporter 2 (hOCT2) activity in a concentration-dependent manner. Thus, these findings suggest that MLE lowered the elimination of Met via inhibiting the hOCT2. Full article
(This article belongs to the Special Issue Pharmacokinetic Drug-Drug Interactions and Herb-Drug Interactions)
Show Figures

Figure 1

Open AccessArticle
In Vitro and In Vivo Assessment of Metabolic Drug Interaction Potential of Dutasteride with Ketoconazole
Pharmaceutics 2019, 11(12), 673; https://doi.org/10.3390/pharmaceutics11120673 - 11 Dec 2019
Cited by 4 | Viewed by 1693
Abstract
Dutasteride (DUT) is a selective, potent, competitive, and irreversible inhibitor of both type-1 and type-2 5α-reductase (5AR) commonly used in the treatment of benign prostatic hyperplasia and androgenetic alopecia. In the present study, we developed a simple and sensitive high-performance liquid chromatography with [...] Read more.
Dutasteride (DUT) is a selective, potent, competitive, and irreversible inhibitor of both type-1 and type-2 5α-reductase (5AR) commonly used in the treatment of benign prostatic hyperplasia and androgenetic alopecia. In the present study, we developed a simple and sensitive high-performance liquid chromatography with fluorescence detection (HPLC-FL) method for simultaneous determination of DUT and its major active metabolite, 6β-hydroxydutasteride (H-DUT). Next, the pharmacokinetic interactions of DUT with ketoconazole (KET), a potent CYP3A inhibitor, were comprehensively investigated. In vivo rat intravenous and oral studies revealed that the pharmacokinetics of DUT and H-DUT were significantly altered by the co-administration of KET. Furthermore, the in vitro microsomal metabolism, blood distribution, and protein-binding studies suggest that the altered pharmacokinetics of DUT could be attributed primarily to the inhibition of the DUT metabolism by KET. To the best of our knowledge, this is the first study to show the drug interaction potential of DUT with azole antifungal drugs including KET, together with a newly developed HPLC-FL method for the simultaneous quantification of DUT and H-DUT. Full article
(This article belongs to the Special Issue Pharmacokinetic Drug-Drug Interactions and Herb-Drug Interactions)
Show Figures

Figure 1

Open AccessArticle
Paradoxical Effect of Grape Pomace Extract on Cisplatin-Induced Acute Kidney Injury in Rats
Pharmaceutics 2019, 11(12), 656; https://doi.org/10.3390/pharmaceutics11120656 - 06 Dec 2019
Cited by 1 | Viewed by 945
Abstract
Cisplatin is one of the most used drugs in the therapy of different types of cancer. However, its use is limited by nephrotoxicity. This study investigated the effects of a commercially available grape pomace extract (GE) from Vitis vinifera on cisplatin-induced kidney toxicity [...] Read more.
Cisplatin is one of the most used drugs in the therapy of different types of cancer. However, its use is limited by nephrotoxicity. This study investigated the effects of a commercially available grape pomace extract (GE) from Vitis vinifera on cisplatin-induced kidney toxicity in rats. Sixty-four male Wistar albino rats were randomly divided into eight groups. Groups 1–3 were controls, receiving 0.9% saline and doses 1 and 2 of GE respectively. Cisplatin was given to groups 4–8. Two groups received pretreatment with GE, while another two groups received pre- and post-treatment with GE. Blood samples were collected and all animals sacrificed. Kidneys were harvested for histopathological analysis. GE significantly increased blood creatinine and urea levels, the severity of kidney histopathological damage, and mortality in all cisplatin groups, except for group 7 which received pre- and post-treatment with a low dose of GE. Renal toxicity was determined by mortality and severe histopathological renal lesions. Additionally, the serum total antioxidant capacity (TAC) was not significantly modified in the treated groups compared to the control. These results indicate that the GE did not have a protective effect on cisplatin-induced nephrotoxicity; on the contrary, GE accentuated the toxic effect of cisplatin. Full article
(This article belongs to the Special Issue Pharmacokinetic Drug-Drug Interactions and Herb-Drug Interactions)
Show Figures

Graphical abstract

Open AccessArticle
Pharmacokinetics and Novel Metabolite Identification of Tartary Buckwheat Extracts in Beagle Dogs Following Co-Administration with Ethanol
Pharmaceutics 2019, 11(10), 525; https://doi.org/10.3390/pharmaceutics11100525 - 12 Oct 2019
Cited by 3 | Viewed by 1225
Abstract
Alcoholic liver disease (ALD) has become a critical global public health issue worldwide. Tartary buckwheat extracts exhibit potential therapeutic effects against ALD due to its antioxidant and anti-inflammatory activities. However, in vivo pharmacokinetics and metabolite identification of tartary buckwheat extracts have not been [...] Read more.
Alcoholic liver disease (ALD) has become a critical global public health issue worldwide. Tartary buckwheat extracts exhibit potential therapeutic effects against ALD due to its antioxidant and anti-inflammatory activities. However, in vivo pharmacokinetics and metabolite identification of tartary buckwheat extracts have not been clearly elucidated. Accordingly, the current manuscript aimed to investigate pharmacokinetics and to identify novel metabolites in beagle dogs following oral co-administration of tartary buckwheat extracts and ethanol. To support pharmacokinetic study, a simple LC-MS/MS method was developed and validated for simultaneous determination of quercetin and kaempferol in beagle dog plasma. The conjugated forms of both analytes were hydrolyzed by β-glucuronidase and sulfatase followed by liquid-liquid extraction using methyl tert-butyl ether. In addition, another effective approach was established using advanced ultrafast liquid chromatography coupled with a Q-Exactive hybrid quadrupole orbitrap high resolution mass spectrometer to identify the metabolites in beagle dog biological samples including urine, feces, and plasma. The pharmacokinetic study demonstrated that the absolute oral bioavailability for quercetin and kaempferol was determined to be 4.6% and 1.6%, respectively. Oral bioavailability of quercetin and kaempferol was limited in dogs probably due to poor absorption, significant first pass effect, and biliary elimination, etc. Using high resolution mass spectrometric analysis, a total of nine novel metabolites were identified for the first time and metabolic pathways included methylation, glucuronidation, and sulfation. In vivo pharmacokinetics and metabolite identification results provided preclinical support of co-administration of tartary buckwheat extracts and ethanol in humans. Full article
(This article belongs to the Special Issue Pharmacokinetic Drug-Drug Interactions and Herb-Drug Interactions)
Show Figures

Graphical abstract

Review

Jump to: Editorial, Research, Other

Open AccessReview
Assessing the Mechanism of Fluoxetine-Mediated CYP2D6 Inhibition
Pharmaceutics 2021, 13(2), 148; https://doi.org/10.3390/pharmaceutics13020148 - 23 Jan 2021
Cited by 2 | Viewed by 539
Abstract
Fluoxetine is still one of the most widely used antidepressants in the world. The drug is extensively metabolized by several cytochrome P450 (CYP450) enzymes and subjected to a myriad of CYP450-mediated drug interactions. In a multidrug regimen, preemptive mitigation of drug–drug interactions requires [...] Read more.
Fluoxetine is still one of the most widely used antidepressants in the world. The drug is extensively metabolized by several cytochrome P450 (CYP450) enzymes and subjected to a myriad of CYP450-mediated drug interactions. In a multidrug regimen, preemptive mitigation of drug–drug interactions requires knowledge of fluoxetine actions on these CYP450 enzymes. The major metabolic pathway of fluoxetine leading to the formation of its active metabolite, norfluoxetine, is mediated by CYP2D6. Fluoxetine and norfluoxetine are strong affinity substrates of CYP2D6 and can inhibit, potentially through various mechanisms, the metabolism of other sensitive CYP2D6 substrates. Remarkably, fluoxetine-mediated CYP2D6 inhibition subsides long after fluoxetine first passes through the liver and even remains long after the discontinuation of the drug. Herein, we review pharmacokinetic and pharmacogenetic information to help us understand the mechanisms underlying the prolonged inhibition of CYP2D6 following fluoxetine administration. We propose that long-term inhibition of CYP2D6 is likely a result of competitive inhibition. This is due to strong affinity binding of fluoxetine and norfluoxetine to the enzyme and unbound fluoxetine and norfluoxetine levels circulating in the blood for a long period of time because of their long elimination half-life. Additionally, we describe that fluoxetine is a CYP2C9 substrate and a mechanism-based inhibitor of CYP2C19. Full article
(This article belongs to the Special Issue Pharmacokinetic Drug-Drug Interactions and Herb-Drug Interactions)
Show Figures

Figure 1

Open AccessReview
Potential Herb–Drug Interactions in the Management of Age-Related Cognitive Dysfunction
Pharmaceutics 2021, 13(1), 124; https://doi.org/10.3390/pharmaceutics13010124 - 19 Jan 2021
Cited by 1 | Viewed by 1402
Abstract
Late-life mild cognitive impairment and dementia represent a significant burden on healthcare systems and a unique challenge to medicine due to the currently limited treatment options. Plant phytochemicals have been considered in alternative, or complementary, prevention and treatment strategies. Herbals are consumed as [...] Read more.
Late-life mild cognitive impairment and dementia represent a significant burden on healthcare systems and a unique challenge to medicine due to the currently limited treatment options. Plant phytochemicals have been considered in alternative, or complementary, prevention and treatment strategies. Herbals are consumed as such, or as food supplements, whose consumption has recently increased. However, these products are not exempt from adverse effects and pharmacological interactions, presenting a special risk in aged, polymedicated individuals. Understanding pharmacokinetic and pharmacodynamic interactions is warranted to avoid undesirable adverse drug reactions, which may result in unwanted side-effects or therapeutic failure. The present study reviews the potential interactions between selected bioactive compounds (170) used by seniors for cognitive enhancement and representative drugs of 10 pharmacotherapeutic classes commonly prescribed to the middle-aged adults, often multimorbid and polymedicated, to anticipate and prevent risks arising from their co-administration. A literature review was conducted to identify mutual targets affected (inhibition/induction/substrate), the frequency of which was taken as a measure of potential interaction. Although a limited number of drugs were studied, from this work, interaction with other drugs affecting the same targets may be anticipated and prevented, constituting a valuable tool for healthcare professionals in clinical practice. Full article
(This article belongs to the Special Issue Pharmacokinetic Drug-Drug Interactions and Herb-Drug Interactions)
Show Figures

Graphical abstract

Open AccessReview
Multifaceted Factors Causing Conflicting Outcomes in Herb-Drug Interactions
Pharmaceutics 2021, 13(1), 43; https://doi.org/10.3390/pharmaceutics13010043 - 30 Dec 2020
Cited by 4 | Viewed by 473
Abstract
Metabolic enzyme and/or transporter-mediated pharmacokinetic (PK) changes in a drug caused by concomitant herbal products have been a primary issue of herb and drug interactions (HDIs), because PK changes of a drug may result in the alternation of efficacy and toxicity. Studies on [...] Read more.
Metabolic enzyme and/or transporter-mediated pharmacokinetic (PK) changes in a drug caused by concomitant herbal products have been a primary issue of herb and drug interactions (HDIs), because PK changes of a drug may result in the alternation of efficacy and toxicity. Studies on HDIs have been carried out by predictive in vitro and in vivo preclinical studies, and clinical trials. Nevertheless, the discrepancies between predictive data and the clinical significance on HDIs still exist, and different reports of HDIs add to rather than clarify the confusion regarding the use of herbal products and drug combinations. Here, we briefly review the underlying mechanisms causing PK-based HDIs, and more importantly summarize challenging issues, such as dose and treatment period effects, to be considered in study designs and interpretations of HDI evaluations. Full article
(This article belongs to the Special Issue Pharmacokinetic Drug-Drug Interactions and Herb-Drug Interactions)
Show Figures

Figure 1

Open AccessReview
Is Antimicrobial Treatment Effective During Therapeutic Plasma Exchange? Investigating the Role of Possible Interactions
Pharmaceutics 2020, 12(5), 395; https://doi.org/10.3390/pharmaceutics12050395 - 25 Apr 2020
Cited by 1 | Viewed by 894
Abstract
Antimicrobial treatment during therapeutic plasma exchange (TPE) remains a complex issue. Recommendations based on a limited number of experimental studies should be implemented in clinical practice with caution. Effective management of infections due to plasma or albumin-related interactions, as well as impaired pharmacokinetics, [...] Read more.
Antimicrobial treatment during therapeutic plasma exchange (TPE) remains a complex issue. Recommendations based on a limited number of experimental studies should be implemented in clinical practice with caution. Effective management of infections due to plasma or albumin-related interactions, as well as impaired pharmacokinetics, in critical illness is difficult. Knowing the pharmacokinetics of the drugs concerned and the procedural aspects of plasmapheresis should be helpful in planning personalized treatment. In general, possessing a low distribution volume, a high protein-binding affinity, a low endogenous clearance rate, and long distribution and elimination half-lives make a drug more prone to elimination during TPE. A high frequency and longer duration of the procedure may also contribute to altering a drug’s concentration. The safest choice would be to start and finish TPE before antimicrobial agent infusion. If this not feasible, a reasonable alternative is to avoid administering the drug just before TPE and to delay the procedure for the time of the administered drug’s distributive phase. Ultimately, if plasma exchange must be performed urgently or the drug has a very narrow therapeutic index, monitoring its plasma concentration is advised. Full article
(This article belongs to the Special Issue Pharmacokinetic Drug-Drug Interactions and Herb-Drug Interactions)
Show Figures

Graphical abstract

Other

Open AccessErratum
Erratum: Choi, Y.H., et al. Multifaceted Factors Causing Conflicting Outcomes in Herb–Drug Interactions. Pharmaceutics 2021, 13, 43
Pharmaceutics 2021, 13(3), 337; https://doi.org/10.3390/pharmaceutics13030337 - 05 Mar 2021
Viewed by 220
Abstract
The authors wish to make the following correction to the funding information [...] Full article
(This article belongs to the Special Issue Pharmacokinetic Drug-Drug Interactions and Herb-Drug Interactions)
Back to TopTop