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Pharmaceutics
Special Issues
Dose-Dependent Pharmacokinetics and Drug Interactions
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Dose-Dependent Pharmacokinetics and 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 (30 September 2022) | Viewed by 12976

Special Issue Editor

Prof. Dr. So Hee Kim

E-Mail Website
Guest Editor
College of Pharmacy and Research Institute of Pharmaceutical Science and Technology, Ajou University, Suwon 16499, Korea
Interests: dose-dependent/dose-independent pharmacokinetics; first-pass metabolism; pharmacokinetic drug–drug interaction; regulation of drug-metabolizing enzymes; pharmacokinetic changes in animal disease models; physiologically based pharmacokinetic (PBPK) simulation

Special Issue Information

Dear Colleagues,

Identification of pharmacokinetic characteristics of a pharmacologically active compound is a very important process in the non-clinical stage of new drug development before entering clinical trials. In particular, characterizing the dose dependency of a compound provides an important clue to predict its efficacy according to dose increase or decrease in clinical practice. The most frequent causes of dose-dependent pharmacokinetics include transporter involvement in the absorption and saturation of drug metabolism in the gastrointestinal tract and/or liver. To evaluate the saturation of drug metabolism, identification of enzymes involved in the metabolism of the compound should be performed. In particular, if either CYP3A, CYP2C or CYP2D is involved in the metabolism of a biologically active compound or a therapeutic drug, drug interaction is expected when co-administered with other drugs or herbal drugs. Moreover, the disease–drug interactions should also be evaluated, since pathophysiological conditions can cause the changes in ADME of drugs, especially changes in the expression of drug-metabolizing enzymes.

Therefore, the Special Issue is primarily about the investigation of the dose-dependent/dose-independent pharmacokinetics and the causes for dose dependency of a biologically active compound in the non-clinical stage. It covers not only the drug–drug and herb–drug interactions related to drug-metabolizing enzymes and transporters but also disease–drug interactions, along with the mechanistic studies of drug interactions. In addition, the development of methods for quantification of a compound in biological samples, such as plasma, also falls within the scope of this Special Issue.

Prof. Dr. So Hee Kim
Guest Editor

Manuscript Submission Information

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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 2900 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

  • pharmacokinetics
  • dose dependency
  • drug interaction
  • drug-metabolizing enzymes
  • drug transporters
  • disease model
  • bioanalysis of pharmacologically active compounds

Published Papers (5 papers)

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Research

15 pages, 1985 KiB  
Article
Effects of Isosakuranetin on Pharmacokinetic Changes of Tofacitinib in Rats with N-Dimethylnitrosamine-Induced Liver Cirrhosis
by Sung Hun Bae, Hyeon Gyeom Choi, So Yeon Park, Sun-Young Chang, Hyoungsu Kim and So Hee Kim
Pharmaceutics 2022, 14(12), 2684; https://doi.org/10.3390/pharmaceutics14122684 - 1 Dec 2022
Cited by 3 | Viewed by 1663
Abstract
Tofacitinib, a Janus kinase 1 and 3 inhibitor, is used to treat rheumatoid arthritis. It is mainly metabolized by the cytochromes p450 (CYP) 3A1/2 and CYP2C11 in the liver. Chronic inflammation eventually leads to cirrhosis in patients with rheumatoid arthritis. Isosakuranetin (ISN), a [...] Read more.
Tofacitinib, a Janus kinase 1 and 3 inhibitor, is used to treat rheumatoid arthritis. It is mainly metabolized by the cytochromes p450 (CYP) 3A1/2 and CYP2C11 in the liver. Chronic inflammation eventually leads to cirrhosis in patients with rheumatoid arthritis. Isosakuranetin (ISN), a component of Citrus aurantium L., has hepatoprotective effects in rats. This study was performed to determine the effects of ISN on the pharmacokinetics of tofacitinib in rats with N-dimethylnitrosamine-induced liver cirrhosis (LC). After intravenous administration of 10 mg/kg tofacitinib to control (CON), LC, and LC treated with ISN (LC-ISN) rats, the total area under the plasma concentration–time curves (AUC) from time zero to infinity increased by 158% in LC rats compared to those in CON rats; however, the AUC of LC-ISN rats decreased by 35.1% compared to that of LC rat. Similar patterns of AUC changes were observed in the LC and LC-ISN rats after oral administration of 20 mg/kg tofacitinib. These results can be attributed to decreased non-renal clearance (CLNR) and intestinal intrinsic clearance (CLint) in the LC rats and increased intestinal and hepatic CLint in the LC-ISN rats. Our findings imply that ISN treatment in LC rats restored the decrease in either CLNR or CLint, or both, through increased hepatic and intestinal expression of CYP3A1/2 and CYP2C11, which is regulated by the induction of pregnane X receptor (PXR) and constitutive androstane receptor (CAR). Full article
(This article belongs to the Special Issue Dose-Dependent Pharmacokinetics and Drug Interactions)
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13 pages, 1401 KiB  
Article
Population Pharmacokinetics of Doxycycline, Administered Alone or with N-Acetylcysteine, in Chickens with Experimental Mycoplasma gallisepticum Infection
by Tsvetelina Petkova, Antoaneta Yordanova and Aneliya Milanova
Pharmaceutics 2022, 14(11), 2440; https://doi.org/10.3390/pharmaceutics14112440 - 11 Nov 2022
Cited by 2 | Viewed by 1659
Abstract
Mycoplasmosis is a bacterial infection that significantly affects poultry production, and it is often controlled with antibiotics, including doxycycline. The conducted study aimed to determine population pharmacokinetic (PopPk) parameters of doxycycline in healthy (n = 12) and in Mycoplasma gallisepticum-challenged (n = [...] Read more.
Mycoplasmosis is a bacterial infection that significantly affects poultry production, and it is often controlled with antibiotics, including doxycycline. The conducted study aimed to determine population pharmacokinetic (PopPk) parameters of doxycycline in healthy (n = 12) and in Mycoplasma gallisepticum-challenged (n = 20) chickens after its oral administration via drinking water at the registered dose rate of 20 mg/kg b.w./24 h for five days, without or with co-administration of N-acetylcysteine (NAC, a dose of 100 mg/kg b.w./24 h) via the feed. Doxycycline concentrations in plasma were analyzed with the LC-MS/MS method. The values of tvV/F and tvke were 4.73 L × kg−1 and 0.154 h−1, respectively, and they showed low BSV. A high BSV of 93.17% was calculated for the value of tlag of 0.8 h, which reflects the inter-individual differences in the water consumption. PTA was computed after Monte Carlo simulation with the registered dose for doxycycline. The target of %fT > MIC ≥ 80% and 100% can be achieved in 90% of the broiler population, after a correction for protein binding, for bacteria with MIC ≤ 0.5 mg × L−1 and 0.25 mg × L−1, respectively. The applied PopPk model did not reveal significant effect of M. gallisepticum infection and co-administration of NAC on pharmacokinetic parameters of doxycycline. Full article
(This article belongs to the Special Issue Dose-Dependent Pharmacokinetics and Drug Interactions)
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19 pages, 1446 KiB  
Article
A Physiologically Based Pharmacokinetic and Pharmacodynamic Model of the CYP3A4 Substrate Felodipine for Drug–Drug Interaction Modeling
by Laura Maria Fuhr, Fatima Zahra Marok, Maximilian Mees, Felix Mahfoud, Dominik Selzer and Thorsten Lehr
Pharmaceutics 2022, 14(7), 1474; https://doi.org/10.3390/pharmaceutics14071474 - 15 Jul 2022
Cited by 6 | Viewed by 2813
Abstract
The antihypertensive felodipine is a calcium channel blocker of the dihydropyridine type, and its pharmacodynamic effect directly correlates with its plasma concentration. As a sensitive substrate of cytochrome P450 (CYP) 3A4 with high first-pass metabolism, felodipine shows low oral bioavailability and is susceptible [...] Read more.
The antihypertensive felodipine is a calcium channel blocker of the dihydropyridine type, and its pharmacodynamic effect directly correlates with its plasma concentration. As a sensitive substrate of cytochrome P450 (CYP) 3A4 with high first-pass metabolism, felodipine shows low oral bioavailability and is susceptible to drug–drug interactions (DDIs) with CYP3A4 perpetrators. This study aimed to develop a physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) parent–metabolite model of felodipine and its metabolite dehydrofelodipine for DDI predictions. The model was developed in PK-Sim® and MoBi® using 49 clinical studies (94 plasma concentration–time profiles in total) that investigated different doses (1–40 mg) of the intravenous and oral administration of felodipine. The final model describes the metabolism of felodipine to dehydrofelodipine by CYP3A4, sufficiently capturing the first-pass metabolism and the subsequent metabolism of dehydrofelodipine by CYP3A4. Diastolic blood pressure and heart rate PD models were included, using an Emax function to describe the felodipine concentration–effect relationship. The model was tested in DDI predictions with itraconazole, erythromycin, carbamazepine, and phenytoin as CYP3A4 perpetrators, with all predicted DDI AUClast and Cmax ratios within two-fold of the observed values. The model will be freely available in the Open Systems Pharmacology model repository and can be applied in DDI predictions as a CYP3A4 victim drug. Full article
(This article belongs to the Special Issue Dose-Dependent Pharmacokinetics and Drug Interactions)
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17 pages, 3778 KiB  
Article
Pharmacokinetics and Tissue Distribution of Enavogliflozin in Mice and Rats
by Minyeong Pang, So Yeon Jeon, Min-Koo Choi, Ji-Hyeon Jeon, Hye-Young Ji, Ji-Soo Choi and Im-Sook Song
Pharmaceutics 2022, 14(6), 1210; https://doi.org/10.3390/pharmaceutics14061210 - 7 Jun 2022
Cited by 7 | Viewed by 3051
Abstract
This study investigated the pharmacokinetics and tissue distribution of enavogliflozin, a novel sodium-glucose cotransporter 2 inhibitor that is currently in phase three clinical trials. Enavogliflozin showed dose-proportional pharmacokinetics following intravenous and oral administration (doses of 0.3, 1, and 3 mg/kg) in both mice [...] Read more.
This study investigated the pharmacokinetics and tissue distribution of enavogliflozin, a novel sodium-glucose cotransporter 2 inhibitor that is currently in phase three clinical trials. Enavogliflozin showed dose-proportional pharmacokinetics following intravenous and oral administration (doses of 0.3, 1, and 3 mg/kg) in both mice and rats. Oral bioavailability was 84.5–97.2% for mice and 56.3–62.1% for rats. Recovery of enavogliflozin as parent form from feces and urine was 39.3 ± 3.5% and 6.6 ± 0.7%, respectively, 72 h after its intravenous injection (1 mg/kg), suggesting higher biliary than urinary excretion in mice. Major biliary excretion was also suggested for rats, with 15.9 ± 5.9% in fecal recovery and 0.7 ± 0.2% in urinary recovery for 72 h, following intravenous injection (1 mg/kg). Enavogliflozin was highly distributed to the kidney, which was evidenced by the AUC ratio of kidney to plasma (i.e., 41.9 ± 7.7 in mice following its oral administration of 1 mg/kg) and showed slow elimination from the kidney (i.e., T1/2 of 29 h). It was also substantially distributed to the liver, stomach, and small and large intestine. In addition, the tissue distribution of enavogliflozin after single oral administration was not significantly altered by repeated oral administration for 7 days or 14 days. Overall, enavogliflozin displayed linear pharmacokinetics following intravenous and oral administration, significant kidney distribution, and favorable biliary excretion, but it was not accumulated in the plasma and major distributed tissues, following repeated oral administration for 2 weeks. These features may be beneficial for drug efficacy. However, species differences between rats and mice in metabolism and oral bioavailability should be considered as drug development continues. Full article
(This article belongs to the Special Issue Dose-Dependent Pharmacokinetics and Drug Interactions)
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10 pages, 1217 KiB  
Article
Pharmacokinetics of DA-6886, A New 5-HT4 Receptor Agonist, in Rats
by Dae Young Lee and Hee Eun Kang
Pharmaceutics 2022, 14(4), 702; https://doi.org/10.3390/pharmaceutics14040702 - 25 Mar 2022
Cited by 1 | Viewed by 1945
Abstract
DA-6886 is a novel serotonin (5-hydroxytrypamine [5-HT]) receptor 4 agonist for the potential treatment of constipation-predominant irritable bowel syndrome. The purpose of this study was to validate the quantitative assay of DA-6886 in rat plasma and to evaluate the pharmacokinetics and tissue distribution [...] Read more.
DA-6886 is a novel serotonin (5-hydroxytrypamine [5-HT]) receptor 4 agonist for the potential treatment of constipation-predominant irritable bowel syndrome. The purpose of this study was to validate the quantitative assay of DA-6886 in rat plasma and to evaluate the pharmacokinetics and tissue distribution of DA-6886 in rats. The liquid chromatography–tandem mass spectrometry (LC–MS/MS) method for the robust quantification of DA-6886 in rat plasma was successfully validated and applied to the pharmacokinetic studies in rats. The pharmacokinetic parameters of DA-6886 in rats were evaluated following single intravenous or oral administration at three dose levels (2, 10, and 20 mg/kg). DA-6886 exhibited a smaller dose-normalized area under the plasma concentration–time curve (AUC) values and faster clearances in the low-dose group than in the high-dose group following both intravenous and oral administration. The steady-state volume of distribution (Vss) of DA-6886 was relatively large (4.91–7.84 L/kg), which was consistent with its high distribution to the liver, kidney, lung, and digestive tract, and was dose-independent. After oral administration, the extent of absolute bioavailability (F) tended to increase (18.9–55.0%) with an increasing dose. The slope of the log-transformed AUC and/or Cmax values versus log dose was greater than unity and greater for oral administration (~1.9) than for intravenous administration (~1.1). Because the nonlinear pharmacokinetics of DA-6886 was more obviously observed after oral administration, it appears that the saturation of pre-systemic intestinal and/or hepatic first-pass extraction of DA-6886 at high doses occurred. Full article
(This article belongs to the Special Issue Dose-Dependent Pharmacokinetics and Drug Interactions)
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