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Pharmaceutics
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Pharmacokinetics of Orally Administered Drugs, 2nd Edition
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Pharmacokinetics of Orally Administered Drugs, 2nd Edition

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

Deadline for manuscript submissions: closed (31 January 2024) | Viewed by 7201

Special Issue Editors

Prof. Dr. Márcio Rodrigues

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Guest Editor
Research Unit for Inland Development (UDI), Polytechnic Institute of Guarda, Av. Dr. Francisco Sá Carneiro, 50, 6300-559 Guarda, Portugal
Interests: pharmacology; pharmacokinetics; bioanalysis; bioavailability; drug delivery; preclinical studies
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Gilberto Alves

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Guest Editor
CICS-UBI—Health Sciences Research Centre, University of Beira Interior, Av. Infante D. Henrique, 6200-506 Covilhã, Portugal
Interests: pharmacokinetics; ADME; bioavailability; drug evaluation; drug delivery; systemic drug exposure
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Oral administration has been the most common route of administration of medicines since it offers the greatest convenience to the patients. Even during the drug discovery process, a frequent requirement is that compounds should enable an adequate systemic exposure via the oral route. However, there are several factors that limit its oral bioavailability, such as poor aqueous solubility, hydrolysis of the drug in the gastrointestinal tract, limited permeability, particle size, extensive intestinal and hepatic first-pass metabolism, high affinity for efflux transporters, and the food effect, among others. To overcome these issues, several strategies have been explored to enhance oral bioavailability and thus systemic drug exposure, but further developments are needed. Therefore, the main goal of this editorial issue is to gather scientific information regarding the latest evidence and recent advances in this field, including the (nano)pharmaceutical approaches that have been explored to improve the bioavailability and pharmacokinetic profile of orally administered drugs.

Prof. Dr. Márcio Rodrigues
Prof. Dr. Gilberto Alves
Guest Editors

Manuscript Submission Information

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Keywords

  • oral bioavailability
  • absorption
  • pharmacokinetics
  • drug delivery
  • formulation

Related Special Issue

Published Papers (6 papers)

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Research

15 pages, 5511 KiB  
Article
Validated LC-MS/MS Assay for the Quantitative Determination of Fenretinide in Plasma and Tumor and Its Application in a Pharmacokinetic Study in Mice of a Novel Oral Nanoformulation of Fenretinide
by Cristina Matteo, Isabella Orienti, Adriana Eramo, Ann Zeuner, Mariella Ferrari, Alice Passoni, Renzo Bagnati, Marianna Ponzo, Ezia Bello, Massimo Zucchetti and Roberta Frapolli
Pharmaceutics 2024, 16(3), 387; https://doi.org/10.3390/pharmaceutics16030387 - 12 Mar 2024
Viewed by 644
Abstract
We describe the development and validation of a HPLC-MS/MS method to assess the pharmacokinetics and tumor distribution of fenretinide, a synthetic retinoid chemically related to all-trans-retinoic acid, after administration of a novel oral nanoformulation of fenretinide, called bionanofenretinide (BNF). BNF was developed to [...] Read more.
We describe the development and validation of a HPLC-MS/MS method to assess the pharmacokinetics and tumor distribution of fenretinide, a synthetic retinoid chemically related to all-trans-retinoic acid, after administration of a novel oral nanoformulation of fenretinide, called bionanofenretinide (BNF). BNF was developed to overcome the major limitation of fenretinide: its poor aqueous solubility and bioavailability due to its hydrophobic nature. The method proved to be reproducible, precise and highly accurate for the measurement of the drug and the main metabolites. The lower limit of quantification resulted in 1 ng/mL. The curve range of 1–500 ng/mL and 50–2000 ng/mL, for plasma and tumor homogenate, respectively, was appropriate for the analysis, as demonstrated by the accuracy of between 96.8% and 102.4% for plasma and 96.6 to 102.3% for the tumor. The interdays precision and accuracy determined on quality controls at three different levels were in the ranges of 6.9 to 7.5% and 99.3 to 101.0%, and 0.96 to 1.91% and 102.3 to 105.8% for plasma and tumor, respectively. With the application of the novel assay in explorative pharmacokinetic studies, following acute and chronic oral administration of the nanoformulation, fenretinide was detected in plasma and tumor tissue at a concentration higher than the IC50 value necessary for in vitro inhibitory activity (i.e., 1–5 µM) in different cancer cells lines. We were also able to detect the presence in plasma and tumor of active and inactive metabolites of fenretinide. Full article
(This article belongs to the Special Issue Pharmacokinetics of Orally Administered Drugs, 2nd Edition)
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17 pages, 3307 KiB  
Article
The Development of an Oral Solution Containing Nirmatrelvir and Ritonavir and Assessment of Its Pharmacokinetics and Stability
by Lili Wang, Zhuang Ding, Zhengping Wang, Yanna Zhao, Hengqian Wu, Qipeng Wei, Lingfeng Gao and Jun Han
Pharmaceutics 2024, 16(1), 109; https://doi.org/10.3390/pharmaceutics16010109 - 14 Jan 2024
Viewed by 915
Abstract
Paxlovid®, a co-packaged medication comprised of separate tablets containing two active ingredients, nirmatrelvir (NRV) and ritonavir (RTV), exhibits good effectiveness against coronavirus disease 2019 (COVID-19). However, the size of the NRV/RTV tablets makes them difficult for some patients to swallow, especially [...] Read more.
Paxlovid®, a co-packaged medication comprised of separate tablets containing two active ingredients, nirmatrelvir (NRV) and ritonavir (RTV), exhibits good effectiveness against coronavirus disease 2019 (COVID-19). However, the size of the NRV/RTV tablets makes them difficult for some patients to swallow, especially the elderly and those with dysphagia. Therefore, an oral liquid formulation that can overcome this shortcoming and improve patient compliance is required. In this study, we developed a liquid formulation containing NRV and RTV by adopting strategies that used co-solvents and surfactants to enhance the solubility and inhibit possible recrystallization. The in vitro release results showed that NRV and RTV could be maintained at high concentrations in solution for a certain period in the investigated media. In vivo studies in rats showed that the oral bioavailability of NRV/RTV solution was significantly enhanced. Compared to Paxlovid® tablets, the AUC(0–t) of NRV and RTV increased by 6.1 and 3.8 times, respectively, while the Cmax increased by 5.5 times for both. Furthermore, the promoting effect of the absorption of RTV on the bioavailability of NRV was confirmed. Experiments with a beagle showed a similar trend. Stability studies were also conducted at 4 °C, 25 °C, and 40 °C for 90 days, indicating that the oral liquid formulation was physically and chemically stable. This study can be used as a valuable resource for developing and applying oral liquid NRV/RTV formulations in a clinical context. Full article
(This article belongs to the Special Issue Pharmacokinetics of Orally Administered Drugs, 2nd Edition)
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18 pages, 2415 KiB  
Article
Improved Pharmacokinetic Feasibilities of Mirabegron-1,2-Ethanedisulfonic Acid, Mirabegron-1,5-Naphthalenedisulfonic Acid, and Mirabegron-L-Pyroglutamic Acid as Co-Amorphous Dispersions in Rats and Mice
by Seo-Yeon Kim, Byung Hoon You, Mingoo Bae, Seung Yon Han, Kiwon Jung and Young Hee Choi
Pharmaceutics 2023, 15(9), 2277; https://doi.org/10.3390/pharmaceutics15092277 - 04 Sep 2023
Cited by 1 | Viewed by 923
Abstract
Mirabegron (MBR) is a β3-adrenoceptor agonist used for treating overactive bladder syndrome. Due to its poor solubility and low bioavailability (F), the development of novel MBR formulations has garnered increasing attention. Recently, co-amorphous dispersions of MBR, such as MBR-1,2-ethanedisulfonic [...] Read more.
Mirabegron (MBR) is a β3-adrenoceptor agonist used for treating overactive bladder syndrome. Due to its poor solubility and low bioavailability (F), the development of novel MBR formulations has garnered increasing attention. Recently, co-amorphous dispersions of MBR, such as MBR-1,2-ethanedisulfonic acid (MBR-EFA), MBR-1,5-naphthalenedisulfonic acid (MBR-NDA), and MBR-L-pyroglutamic acid (MBR-PG), have been developed, showing improved solubility and thermodynamic stability. Nevertheless, the pharmacokinetic feasibility of these co-amorphous dispersions has not been evaluated. Therefore, this study aimed to characterize the pharmacokinetic profiles of MBR-EFA, MBR-NDA, and MBR-PG in rats and mice. Our results exhibited that relative F24h and AUC0–24h values of MBR in MBR-EFA, MBR-NDA, and MBR-PG rats were increased by 143–195% compared with the MBR rats. The absolute F24h, relative F24h, and AUC0–24h values of MBR in MBR-EFA and MBR-NDA mice were enhanced by 178–234% compared with the MBR mice. In tissue distribution, MBR was extensively distributed in the gastrointestinal tract, liver, kidneys, lung, and heart of mice. Notably, MBR distribution in the liver, kidneys, and lung was considerably high in MBR-EFA, MBR-NDA, or MBR-PG mice compared with MBR mice. These findings highlight the potential of these co-amorphous dispersions to enhance oral F of MBR. Full article
(This article belongs to the Special Issue Pharmacokinetics of Orally Administered Drugs, 2nd Edition)
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16 pages, 1757 KiB  
Article
Evaluation of Pharmacokinetic Feasibility of Febuxostat/L-pyroglutamic Acid Cocrystals in Rats and Mice
by Jeong-Eun Yu, Byoung Hoon You, Mingoo Bae, Seung Yon Han, Kiwon Jung and Young Hee Choi
Pharmaceutics 2023, 15(8), 2167; https://doi.org/10.3390/pharmaceutics15082167 - 21 Aug 2023
Viewed by 898
Abstract
Febuxostat (FBX), a selective xanthine oxidase inhibitor, belongs to BCS class II, showing low solubility and high permeability with a moderate F value (<49%). Recently, FBX/L-pyroglutamic acid cocrystal (FBX-PG) was developed with an improving 4-fold increase of FBX solubility. Nevertheless, the in vivo [...] Read more.
Febuxostat (FBX), a selective xanthine oxidase inhibitor, belongs to BCS class II, showing low solubility and high permeability with a moderate F value (<49%). Recently, FBX/L-pyroglutamic acid cocrystal (FBX-PG) was developed with an improving 4-fold increase of FBX solubility. Nevertheless, the in vivo pharmacokinetic properties of FBX-PG have not been evaluated yet. Therefore, the pharmacokinetic feasibility of FBX in FBX- and FBX-PG-treated rats and mice was compared in this study. The results showed that the bioavailability (F) values of FBX were 210% and 159% in FBX-PG-treated rats and mice, respectively. The 2.10-fold greater total area under the plasma concentration–time curve from time zero to infinity (AUC0-inf) of FBX was due to the increased absorption [i.e., 2.60-fold higher the first peak plasma concentration (Cmax,1) at 15 min] and entero-hepatic circulation of FBX [i.e., 1.68-fold higher the second peak plasma concentration (Cmax,2) at 600 min] in FBX-PG-treated rats compared to the FBX-treated rats. The 1.59-fold greater AUC0-inf of FBX was due to a 1.65-fold higher Cmax,1 at 5 min, and a 1.15-fold higher Cmax,2 at 720 min of FBX in FBX-PG-treated mice compared to those in FBX-treated mice. FBX was highly distributed in the liver, stomach, small intestine, and lungs in both groups of mice, and the FBX distributions to the liver and lungs were increased in FBX-PG-treated mice compared to FBX-treated mice. The results suggest the FBX-PG has a suitable pharmacokinetic profile of FBX for improving its oral F value. Full article
(This article belongs to the Special Issue Pharmacokinetics of Orally Administered Drugs, 2nd Edition)
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11 pages, 779 KiB  
Article
A Study on Pharmacokinetics of Acetylsalicylic Acid Mini-Tablets in Healthy Adult Males—Comparison with the Powder Formulation
by Noriko Hida, Taigi Yamazaki, Yoshiaki Fujita, Hidehiro Noda, Takehiko Sambe, Kakei Ryu, Takuya Mizukami, Sachiko Takenoshita, Naoki Uchida, Akihiro Nakamura and Tsutomu Harada
Pharmaceutics 2023, 15(8), 2079; https://doi.org/10.3390/pharmaceutics15082079 - 03 Aug 2023
Viewed by 1577
Abstract
Children with Kawasaki disease are prescribed acetylsalicylic acid powder as an antipyretic analgesic and antiplatelet agent; however, some of it remains in the mouth, leading to a bitter or sour taste. To address this issue, an in-hospital mini-tablet formulation of acetylsalicylic acid was [...] Read more.
Children with Kawasaki disease are prescribed acetylsalicylic acid powder as an antipyretic analgesic and antiplatelet agent; however, some of it remains in the mouth, leading to a bitter or sour taste. To address this issue, an in-hospital mini-tablet formulation of acetylsalicylic acid was developed. In order to use the mini-tablets safely and effectively, dissolution tests alone are not sufficient. Therefore, an open-label crossover study on six healthy participants was conducted to evaluate comparative pharmacokinetic parameters. The pharmacokinetic parameters of salicylic acid were Cmax: 4.80 ± 0.79 mg/L (powder; P), 5.03 ± 0.97 mg/L (mini-tablet; MT), AUC0–12: 18.0 ± 3.03 mg-h/L (P), 18.9 ± 4.59 mg-h/L (MT), those of acetylsalicylic acid Cmax: 0.50 ± 0.20 mg/L (P), 0.41 ± 0.24 mg/L (MT), AUC0–12: 0.71 ± 0.27 mg-h/L (P), 0.61 ± 0.36 mg-h/L (MT), with no significant differences between the mini-tablet and powder formulations. Although pharmacokinetic results obtained from adults cannot be directly applied to children, the results of this study are important for predicting pharmacokinetics. Furthermore, a formulation that can improve medication adherence in children who have difficulty taking acetylsalicylic acid powder, thus contributing to pediatric drug therapy. Full article
(This article belongs to the Special Issue Pharmacokinetics of Orally Administered Drugs, 2nd Edition)
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13 pages, 6091 KiB  
Article
Pharmacokinetic Feasibility of Stability-Enhanced Solid-State (SESS) Tenofovir Disoproxil Free Base Crystal
by Byoung Hoon You, Mingoo Bae, Seung Yon Han, Jieun Jung, Kiwon Jung and Young Hee Choi
Pharmaceutics 2023, 15(5), 1392; https://doi.org/10.3390/pharmaceutics15051392 - 01 May 2023
Cited by 2 | Viewed by 1543
Abstract
Tenofovir (TEV) is a nucleotide reverse transcriptase inhibitor used against human immunodeficiency virus (HIV) reverse transcriptase. To improve the poor bioavailability of TEV, TEV disoproxil (TD), an ester prodrug of TEV, was developed, and TD fumarate (TDF; Viread®) has been marketed [...] Read more.
Tenofovir (TEV) is a nucleotide reverse transcriptase inhibitor used against human immunodeficiency virus (HIV) reverse transcriptase. To improve the poor bioavailability of TEV, TEV disoproxil (TD), an ester prodrug of TEV, was developed, and TD fumarate (TDF; Viread®) has been marketed due to the hydrolysis of TD in moisture. Recently, a stability-enhanced solid-state TD free base crystal (SESS-TD crystal) was developed with improved solubility (192% of TEV) under gastrointestinal pH condition and stability under accelerated conditions (40 °C, RH 75%) for 30 days. However, its pharmacokinetic property has not been evaluated yet. Therefore, this study aimed to evaluate the pharmacokinetic feasibility of SESS-TD crystal and to determine whether the pharmacokinetic profile of TEV remained unchanged when administering SESS-TD crystal stored for 12 months. In our results, the F and systemic exposure (i.e., AUC and Cmax) of TEV in the SESS-TD crystal and TDF groups were increased compared to those in the TEV group. The pharmacokinetic profiles of TEV between the SESS-TD and TDF groups were comparable. Moreover, the pharmacokinetic profiles of TEV remained unchanged even after the administration of the SESS-TD crystal and TDF stored for 12 months. Based on the improved F after the SESS-TD crystal administration and the stable condition of the SESS-TD crystal after 12 months, SESS-TD crystal may have enough pharmacokinetic feasibility to replace TDF. Full article
(This article belongs to the Special Issue Pharmacokinetics of Orally Administered Drugs, 2nd Edition)
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