Pharmacotherapy for Keloids and Hypertrophic Scars.

Keloids (KD) and hypertrophic scars (HTS), which are quite raised and pigmented and have increased vascularization and cellularity, are formed due to the impaired healing process of cutaneous injuries in some individuals having family history and genetic factors. These scars decrease the quality of life (QOL) of patients greatly, due to the pain, itching, contracture, cosmetic problems, and so on, depending on the location of the scars. Treatment/prevention that will satisfy patients' QOL is still under development. In this article, we review pharmacotherapy for treating KD and HTS, including the prevention of postsurgical recurrence (especially KD). Pharmacotherapy involves monotherapy using a single drug and combination pharmacotherapy using multiple drugs, where drugs are administered orally, topically and/or through intralesional injection. In addition, pharmacotherapy for KD/HTS is sometimes combined with surgical excision and/or with physical therapy such as cryotherapy, laser therapy, radiotherapy including brachytherapy, and silicone gel/sheeting. The results regarding the clinical effectiveness of each mono-pharmacotherapy for KD/HTS are not always consistent but rather scattered among researchers. Multimodal combination pharmacotherapy that targets multiple sites simultaneously is more effective than mono-pharmacotherapy. The literature was searched using PubMed, Google Scholar, and Online search engines.

Comparison of Berberine Bioavailability between Oral and Rectal Administrations in Rats.

The oral bioavailability of berberine is quite low due to extensive first-pass metabolism. To increase the bioavailability of berberine (BBR), the efficacy of rectal administration that can avoid intestinal and hepatic first-pass metabolism partly was evaluated using BBR sulfate in rats. BBR sulfate was administered intravenously (1 mg/kg as BBR), orally (10 mg/kg as BBR) and rectally (1, 3, or 10 mg/kg as BBR) using Witepsol® H15 suppository base to evaluate bioavailability in rats. Concentrations of BBR in plasma were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS). When BBR sulfate was administered orally, the average oral bioavailability was 0.26%. When BBR sulfate was administered rectally, the average bioavailabilities were 17.0% at 1 mg/kg, 24.3% at 3 mg/kg, and 12.3% at 10 mg/kg as BBR, respectively. Thus, rectal administration of BBR sulfate greatly increased the bioavailability of BBR as compared with oral administration, which would also increase the pharmacological activities of BBR in vivo.

Development and Evaluation of EDTA-Treated Rabbits for Bioavailability Study of Chelating Drugs Using Levofloxacin, Ciprofloxacin, Hemiacetal Ester Prodrugs, and Tetracycline.

Laboratory rabbits are fed foods rich with cationic metals, and while fasting cannot empty gastric contents because of their coprophagic habits. This implies that, in rabbits, the oral bioavailability of chelating drugs could be modulated by the slow gastric emptying rates and the interaction (chelation, adsorption) with gastric metals. In the present study, we tried to develop a rabbit model with low amounts of cationic metals in the stomach for preclinical oral bioavailability studies of chelating drugs. The elimination of gastric metals was achieved by preventing food intake and coprophagy and administering a low concentration of EDTA 2Na solution one day before experiments. Control rabbits were fasted but coprophagy was not prevented. The efficacy of rabbits treated with EDTA 2Na was evaluated by comparing the gastric contents, gastric metal contents and gastric pH between EDTA-treated and control rabbits. The treatment with more than 10 mL of 1 mg/mL EDTA 2Na solution decreased the amounts of gastric contents, cationic metals and gastric pH, without causing mucosal damage. The absolute oral bioavailabilities (mean values) of levofloxacin (LFX), ciprofloxacin (CFX) and tetracycline hydrochloride (TC), chelating antibiotics, were significantly higher in EDTA-treated rabbits than those in control rabbits as follows: 119.0 vs. 87.2%, 9.37 vs. 13.7%, and 4.90 vs. 2.59%, respectively. The oral bioavailabilities of these drugs were significantly decreased when Al(OH)3 was administered concomitantly in both control and EDTA-treated rabbits. In contrast, the absolute oral bioavailabilities of ethoxycarbonyl 1-ethyl hemiacetal ester (EHE) prodrugs of LFX and CFX (LFX-EHE, CFX-EHE), which are non-chelating prodrugs at least in in vitro condition, were comparable between control and EDTA-treated rabbits irrespective of the presence of Al(OH)3, although some variation was observed among rabbits. The oral bioavailabilities of LFX and CFX from their EHE prodrugs were comparable with LFX and CFX alone, respectively, even in the presence of Al(OH)3. In conclusion, LFX, CFX and TC exhibited higher oral bioavailabilities in EDTA-treated rabbits than in control rabbits, indicating that the oral bioavailabilities of these chelating drugs are reduced in untreated rabbits. In conclusion, EDTA-treated rabbits were found to exhibit low gastric contents including metals and low gastric pH, without causing mucosal damage. Ester prodrug of CFX was effective in preventing chelate formation with Al(OH)3 in vitro and in vivo, as well as in the case of ester prodrugs of LFX. EDTA-treated rabbits are expected to provide great advantages in preclinical oral bioavailability studies of various drugs and dosage formulations. However, a marked interspecies difference was still observed in the oral bioavailability of CFX and TC between EDTA-treated rabbits and humans, possibly due to the contribution of adsorptive interaction in rabbits. Further study is necessary to seek out the usefulness of the EDTA-treated rabbit with less gastric contents and metals as an experimental animal.

Approaching strategy to increase the oral bioavailability of berberine, a quaternary ammonium isoquinoline alkaloid: part 2. development of oral dosage formulations.

INTRODUCTION: Berberine (BBR) possesses a wide variety of pharmacological activities. However, the oral bioavailability of BBR is low due to extensive intestinal first-pass metabolism by cytochrome P450s (CYPs), insufficient absorption due to low solubility and P-glycoprotein (P-gp)-mediated efflux transport, and hepatic first-pass metabolism in rats. AREAS COVERED: Various dosage formulations were developed to increase the oral bioavailability of BBR by overcoming the reducing factors. This article provides the developing strategy of oral dosage formulations of BBR based on the physicochemical (low solubility, formation of salts/ion-pair complex) and pharmacokinetic properties (substrate of P-gp/CYPs, extensive intestinal first-pass metabolism). Literature was searched using PubMed. EXPERT OPINION: Here, formulations increasing the dissolution rates/solubility; formulations containing a P-gp inhibitor; formulations containing solubilizer exhibiting P-gp and/or CYPs inhibitors; formulations containing absorption enhancers; gastro/duodenal retentive formulations; lipid-based formulations; formulations targeting lymphatic transport; and physicochemical modifications increasing lipophilicity were reviewed. Among these formulations, formulations that can reduce intestinal first-pass metabolisms such as formulations containing CYPs inhibitor(s) and formulations containing absorption enhancer(s) significantly increased the oral bioavailability of BBR. Further studies on other dosing routes that can avoid first-pass metabolism such as the rectal route would also be important to increase the bioavailability of BBR.

Approaching strategy to increase the oral bioavailability of berberine, a quaternary ammonium isoquinoline alkaloid: Part 1. Physicochemical and pharmacokinetic properties.

INTRODUCTION: Berberine (BBR), a quaternary ammonium isoquinoline alkaloid, is a substrate for P-glycoprotein (P-gp) and cytochrome P450s (CYPs). BBR exhibits a wide variety of pharmacological activities; however, its clinical application is limited due to low oral bioavailability. AREAS COVERED: Physicochemical and pharmacokinetic properties of BBR and its lipophilic metabolites, berberrubine (BRB) and dihydroberberine (DHBBR), were reviewed including solubility/lipophilicity, salt/ion-pair formation, oral bioavailability, first-pass metabolism, and intestinal microbiota-mediated metabolism, by searching research articles using PubMed. EXPERT OPINION: Pharmacokinetic analysis of BBR bioavailability data in rats revealed that the oral bioavailability is limited by the extensive CYPs-mediated intestinal first-pass metabolism, insufficient membrane permeability due to the low solubility and P-gp-mediated efflux transport, and the hepatic first-pass metabolism. Various active metabolites are generated by intestinal first-pass metabolism. Intestinal microbiota also contributes to the BBR metabolism and generates lipophilic metabolites; BRB, an active metabolite, and DHBBR, a precursor that can distribute to the brain. The pharmacokinetic analysis of BBR bioavailability data can provide a clue to developing effective dosage routes and/or formulations that can increase the oral bioavailability of BBR.

Diagnosis by Microbial Culture, Breath Tests and Urinary Excretion Tests, and Treatments of Small Intestinal Bacterial Overgrowth.

Small intestinal bacterial overgrowth (SIBO) is characterized as the increase in the number and/or alteration in the type of bacteria in the upper gastrointestinal tract and accompanies various bowel symptoms such as abdominal pain, bloating, gases, diarrhea, and so on. Clinically, SIBO is diagnosed by microbial culture in duodenum/jejunum fluid aspirates and/or the breath tests (BT) of hydrogen/methane gases after ingestion of carbohydrates such as glucose. The cultural analysis of aspirates is regarded as the golden standard for the diagnosis of SIBO; however, this is invasive and is not without risk to the patients. BT is an inexpensive and safe diagnostic test but lacks diagnostic sensitivity and specificity depending on the disease states of patients. Additionally, the urinary excretion tests are used for the SIBO diagnosis using chemically synthesized bile acid conjugates such as cholic acid (CA) conjugated with para-aminobenzoic acid (PABA-CA), ursodeoxycholic acid (UDCA) conjugated with PABA (PABA-UDCA) or conjugated with 5-aminosalicylic acid (5-ASA-UDCA). These conjugates are split by bacterial bile acid (cholylglycine) hydrolase. In the tests, the time courses of the urinary excretion rates of PABA or 5-ASA, including their metabolites, are determined as the measure of hydrolytic activity of intestinal bacteria. Although the number of clinical trials with this urinary excretion tests is small, results demonstrated the usefulness of bile acid conjugates as SIBO diagnostic substrates. PABA-UDCA disulfate, a single-pass type unabsorbable compound without the hydrolysis of conjugates, was likely to offer a simple and rapid method for the evaluation of SIBO without the use of radioisotopes or expensive special apparatus. Treatments of SIBO with antibiotics, probiotics, therapeutic diets, herbal medicines, and/or fecal microbiota transplantation are also reviewed.

Study on the method to avoid infusion-site adverse events following chemotherapeutic treatment with epirubicin and fosaprepitant using immortalized human umbilical vein endothelial cells.

The combination of intravenous Proemend® containing fosaprepitant meglumine, a prodrug for fosaprepitant (FAP), and Tween 80 and chemotherapy with anthracyclines, such as epirubicin (EPI), can cause infusion-site adverse events in clinical practice. In immortalized human umbilical vein endothelial (HUEhT-1) cells, the cytotoxic effects of FAP, EPI, diluted Proemend with culture medium and Tween 80 alone, and a combination of FAP and EPI, were evaluated using the WST-1 cell viability assay. FAP, EPI and diluted Proemend exhibited cytotoxicity in a concentration-dependent manner and marked synergic cytotoxicity was observed between FAP and EPI. The washing of the cell surface following incubation with diluted Proemend containing FAP and Tween-80 eliminated the synergic cytotoxicity of EPI applied thereafter. These results indicated that washing of the infusion-site vascular tissue following intravenous Proemend administration via intravenous tube flushing with an efficient amount of saline may reduce the infusion-site adverse events, which are caused by the combined use of FAP and EPI.

Factors and dosage formulations affecting the solubility and bioavailability of P-glycoprotein substrate drugs.

Introduction: Expression of P-glycoprotein (P-gp) increases toward the distal small intestine, implying that the duodenum is the preferential absorption site for P-gp substrate drugs. Oral bioavailability of poorly soluble P-gp substrate drugs is low and varied but increases with high-fat meals that supply lipoidal components and bile in the duodenum.Areas covered: Absorption properties of P-gp substrate drugs along with factors and oral dosage formulations affecting their solubility and bioavailability were reviewed with PubMed literature searches. An overview is provided from the viewpoint of the 'spring-and-parachute approach' that generates supersaturation of poorly soluble P-gp substrate drugs.Expert opinion: The oral bioavailability of P-gp substrate drugs is difficult to predict because of their low solubility, preferential absorption sites, and overlapping substrate specificities with CYP3A4, along with the scattered intestinal P-gp expression/function. To attain high and steady oral bioavailability of poorly soluble P-gp substrate drugs, physicochemical modification of drugs to improve solubility, or oral dosage formulations that generate long-lasting supersaturation in the duodenum, is preferred. In particular, supersaturable lipid-based drug delivery systems that can increase passive diffusion and/or lymphatic absorption are effective and applicable to many poorly soluble P-gp substrate drugs.

Modulation of expression/function of intestinal P-glycoprotein under disease states.

Introduction: ATP-binding cassette (ABC) transporters, especially P-glycoprotein (P-gp), and various metabolic enzymes, in particular, CYP3A, expressed in the small intestine cooperatively limit the absorption of orally administered P-gp substrate drugs. The expression and/or function of intestinal P-gp, however, is easily modulated by various factors.Areas covered: Through extensive literature searches primarily utilizing PubMed, the authors reviewed factors that may cause inter- or intra-individual variations of the pharmacokinetics of orally administered P-gp substrate drugs due to the modulation of intestinal P-gp expression/function. The information on P-gp modulating factors can help to develop safer and more reliable oral formulations and pharmacotherapy.Expert opinion: In clinical pharmacotherapy with orally administered P-gp substrate drugs, the pharmacological action may exhibit a large interindividual variation among patients. Factors modulating intestinal P-gp expression/function listed here include: circadian rhythm (or drug dosing time), drug-drug interactions, formulation/excipients (vehicle, nonionic surfactants), food/supplements, gene polymorphism, obesity, colorectal carcinomas, diarrhea, hepatic failure, inflammation, inflammatory bowel disease, ischemia/reperfusion, organ transplant, renal failure, and others. We will discuss the methods for reducing the effect of modulated intestinal P-gp function on the pharmacokinetics of orally administered P-gp substrate drugs to achieve safer and more reliable oral formulations and pharmacotherapy.

Study on the infusion-site adverse events and vascular distribution of epirubicin in chemotherapy with epirubicin and fosaprepitant.

In breast cancer patients on a fluorouracil-epirubicin (EPI)-cyclophosphamide (FEC) regimen and intravenous fosaprepitant (FAP) during chemotherapy, infusion-site adverse events such as vascular pain and induration and/or phlebitis are observed. In the present study, adverse events induced by the FEC regimen and FAP, a prodrug of aprepitant (AP), were studied based on the vascular tissue distribution of EPI in rats. Rats were treated with intravenous FAP (3 mg/kg, 10 min-constant rate infusion) or oral AP (3 mg/kg) and then intravenous EPI (1 mg/kg, 5 min-constant rate infusion) as follows: FAP-S Group, FAP and then EPI was infused from the same site on the jugular vein; FAP-D Group, FAP and then EPI was infused from different jugular veins (left and right); and AP Group, AP was administered orally and EPI was infused from the jugular vein. Concentrations of EPI in vascular tissue at the EPI infusion sites and opposite sites of the jugular vein (left and right, respectively) were measured at 30 min and 24 h after EPI infusion. Histological observation of the EPI infusion site was also made separately. In rats, the tissue concentrations of EPI at the infusion site in the FAP-S group were higher than those in the FAP-D and AP groups. Inflammation and necrosis were observed at the EPI infusion-site vascular tissue of the FAP-S group, but not of the FAP-D and AP groups. These findings could aid the development of an approach to avoid infusion-site adverse events in anthracycline-based chemotherapy in the clinical practice.

Reduction in the rate of postoperative delirium by switching from famotidine to omeprazole in Japanese hepatectomized recipients.

BACKGROUND: Hepatectomy is a highly invasive procedure with a high probability of postoperative delirium. Treatment with antiulcer drugs is indispensable after hepatectomy for anastomotic ulcer management. The clinical pathway for hepatectomy was reviewed and the antiulcer drug used was switched from famotidine, a H2-receptor antagonist, to omeprazole, a proton pump inhibitor, owing to the pharmacist's intervention. METHODS: Hepatectomized recipients over 65 years of age, except in the cases of laparoscopic surgery and intensive care unit entry, were treated with famotidine injections (10 patients) or omeprazole injections (11 patients), and the incidence rates and severity of delirium were compared between the famotidine and omeprazole groups. The delirium after hepatectomy was assessed using the Japanese version of the NEECHAM confusion scale. RESULTS: The incidence rates of delirium were 90% in the famotidine group and 27.3% in the omeprazole group. Four out of 9 recipients in the famotidine group were injected with haloperidol to treat for delirium, but no recipients needed this treatment in the omeprazole group. CONCLUSIONS: Compared with famotidine, the use of omeprazole was found to be effective in reducing the incidence rate and severity of postoperative delirium in patients undergoing hepatectomy. Pharmacists should actively strive to mitigate the risks of delirium.

Uptake and metabolism of mizoribine, an immunosuppressant, in L5178Y-R mouse lymphoma cells in vitro and peripheral blood mononuclear cells of rats and kidney transplant recipients in vivo.

The cellular uptake of mizoribine (MZR), an immunosuppressant, and metabolism of MZR to MZR-5'- monophosphate (MZRP), an active metabolite, were evaluated in L5178Y-R mouse lymphoma cells and peripheral blood mononuclear cells (PBMCs) of rats and kidney transplant recipients (KTRs, n = 22). Real-time PCR analysis revealed the expression of ENT1 and ENT2 mRNAs, but not of CNTs, in L5178Y-R cells and rat's PBMCs. In L5178Y-R cells, the uptake of MZR was suppressed by adenosine, a substrate for ENT1 and ENT2, but not by 5-(4-nitrobenzyl)-6-thioinosine (0.1 µM), an ENT1 inhibitor. Saturable metabolism of MZR to MZRP was observed. In rats, peak plasma concentrations of MZR and peak concentrations of MZR and MZRP in PBMCs were observed 3 h after oral administration. MZR disappeared from PBMCs in parallel with plasma MZR, but the disappearance of MZRP from PBMCs appeared to be slow. In KTRs, the mean plasma concentration of MZR 3-4 h after ingestion was 3.14 µg/ml and the mean MZRP concentration in PBMCs was 16.8% of MZR, reflecting the involvement of ENT in the uptake of MZR. A linear relationship was observed between plasma MZR concentrations ranging from 1 to 6 µg/ml and PBMC's MZRP concentrations ranging from 90 to 200 ng/ml.

Effect of Gamma Ray Irradiation on Friction Property of Poly(vinyl alcohol) Cast-Drying on Freeze-Thawed Hybrid Gel.

Poly(vinyl alcohol) (PVA) is a biocompatible polymer with low toxicity. It is possible to prepare physically cross-linked PVA gels having hydrogen bonds without using a cross-linking agent. The newly reported physically cross-linked PVA cast-drying (CD) on freeze-thawed (FT) hybrid gel has an excellent friction property, which is expected to be applied as a candidate material for artificial cartilage. Gamma ray sterilization for clinical applications usually causes additional chemical cross-linking and changes physical properties of gels. In this study, CD on FT hybrid gels were irradiated using gamma rays at a different dose rate and irradiance. The results showed the optimized irradiation conditions for gamma irradiated gels to retain excellent friction characteristics.

Pharmacokinetic interaction of green tea beverage containing cyclodextrins and high concentration catechins with P-glycoprotein substrates in LLC-GA5-COL150 cells in vitro and in the small intestine of rats in vivo.

OBJECTIVES: Possible interaction of green tea beverage (GT) containing cyclodextrins and high concentration catechins, a drinking water, with P-glycoprotein (P-gp) substrates was examined in vitro and in vivo. METHODS: Effects of GT on the uptake of rhodamine 123 by LLC-GA5-COL150 cells and intestinal efflux of rhodamine 123 from blood, intestinal absorption of quinidine from ileum loop and oral absorption of digoxin were examined in rats. Effects of GT and GT components on digoxin solubility were also examined. KEY FINDINGS: Green tea increased the uptake of rhodamine 123 by LLC-GA5-COL150 cells, suppressed the intestinal efflux of rhodamine 123 from blood and increased the absorption of quinidine in the ileum of rats. Also, GT increased the solubility of digoxin, and ingestion of GT significantly increased the oral absorption of digoxin given at a high dose in rats. CONCLUSIONS: Green tea suppressed the P-gp-mediated efflux transport of hydrophilic compounds and increased the solubility of lipophilic compounds. Thus, GT may cause interaction with various P-gp substrates, due to the combined effects of catechins and cyclodextrins. Especially, cyclodextrin alone can cause interaction with various low-solubility compounds in vivo. In taking low-solubility drugs including low-solubility P-gp substrates, cyclodextrin-containing foods and beverages such as GT should be avoided.

Absorption sites of orally administered drugs in the small intestine.

INTRODUCTION: In pharmacotherapy, drugs are mostly taken orally to be absorbed systemically from the small intestine, and some drugs are known to have preferential absorption sites in the small intestine. It would therefore be valuable to know the absorption sites of orally administered drugs and the influencing factors. Areas covered:In this review, the author summarizes the reported absorption sites of orally administered drugs, as well as, influencing factors and experimental techniques. Information on the main absorption sites and influencing factors can help to develop ideal drug delivery systems and more effective pharmacotherapies. Expert opinion: Various factors including: the solubility, lipophilicity, luminal concentration, pKa value, transporter substrate specificity, transporter expression, luminal fluid pH, gastrointestinal transit time, and intestinal metabolism determine the site-dependent intestinal absorption. However, most of the dissolved fraction of orally administered drugs including substrates for ABC and SLC transporters, except for some weakly basic drugs with higher pKa values, are considered to be absorbed sequentially from the proximal small intestine. Securing the solubility and stability of drugs prior to reaching to the main absorption sites and appropriate delivery rates of drugs at absorption sites are important goals for achieving effective pharmacotherapy.

Modulation of multidrug resistance-associated proteins function in erythrocytes in glycerol-induced acute renal failure rats.

OBJECTIVES: Evaluation of the function of multidrug resistance-associated proteins (MRPs) expressed in erythrocytes and screening of endogenous MRPs modulator(s) in glycerol-induced acute renal failure (ARF) rats. METHODS: Concentrations of 2,4-dinitrophenyl-S-glutathione (DNP-SG), a substrate for MRPs, in erythrocytes after administration of 1-chloro-2,4-dintrobenzene (CDNB), a precursor of DNP-SG, were determined in control and ARF rats. The screening of endogenous MRPs modulator(s) was performed using washed erythrocytes and inside-out erythrocyte membrane vesicles (IOVs) in vitro. KEY FINDINGS: Accumulation of DNP-SG in erythrocytes was observed in ARF rats. Uraemic plasma components exhibited a greater inhibitory effect on DNP-SG uptake by IOVs than control plasma components and increased the DNP-SG accumulation significantly in washed erythrocytes. Several protein-bound uraemic toxins at clinically observed concentrations and bilirubin significantly inhibited DNP-SG uptake by IOVs. In washed erythrocytes, bilirubin (10 µm) and l-kynurenine (100 µm), a precursor of kynurenic acid being MRPs inhibitor, increased DNP-SG accumulation significantly. CONCLUSIONS: Glycerol-induced ARF rats contain various MRPs inhibitors in plasma, and membrane-permeable MRP substrates/inhibitors including their precursors inhibit the MRPs function in erythrocytes cooperatively.

Dosage Adjustment of Dabigatran Etexilate Based on Creatinine Clearance in Patients With Cardioembolic Stroke or Atrial Fibrillation.

BACKGROUND: A recommendation for dosage adjustment of dabigatran etexilate, a prodrug of dabigatran, seems to be desirable based on creatinine clearance to avoid bleeding and stroke. METHODS: Outpatients and inpatients having a history of cardioembolic stroke or atrial fibrillation were included. After taking dabigatran etexilate orally (75-150 mg twice daily) for at least 1 week, plasma trough concentration (Ctrough, ng/mL) of dabigatran and creatinine clearance (CLcr, mL/min) of patients according to Cockcroft and Gault equation were determined. RESULTS: Among the 38 patients studied, Ctrough of dabigatran and CLcr were scattered in a range from 31.4 to 329.5 ng/mL and 15.4-133.4 mL/min, respectively. Temporal CLtotal (Temp-CLtotal) of dabigatran, estimated by dividing the daily absorbed amount of dabigatran etexilate with Ctrough of dabigatran, was linearly correlated with CLcr of patients (P = 0.0018). Based on the findings, the daily dose of dabigatran etexilate that provides Ctrough of dabigatran at approximately 70 ng/mL was estimated. CONCLUSIONS: A linear relationship was found between Temp-CLtotal of dabigatran and CLcr of patients. Depending on CLxr of patients, we recommend 4 different dosages of dabigatran etexilate to obtain Ctrough of dabigatran at approximately 70 ng/mL.

A Minireview: Usefulness of Transporter-Targeted Prodrugs in Enhancing Membrane Permeability.

Orally administered drugs are categorized into 4 classes depending on the solubility and permeability in a Biopharmaceutics Classification System. Prodrug derivatization is one of feasible approaches in modifying the physicochemical properties such as low solubility and low permeability without changing the in vivo pharmacological action of the parent drug. In this article, prodrug-targeted solute carrier (SLC) transporters were searched randomly by PubMed. Collected SLC transporters are amino acid transporter 1, bile acid transporter, carnitine transporter 2, glucose transporter 1, peptide transporter 1, vitamin C transporter 1, and multivitamin transporter. The usefulness of transporter-targeted prodrugs was evaluated in terms of membrane permeability, stability under acidic condition, and conversion to the parent drug. Among prodrugs collected, peptide transporter-targeted prodrugs exhibited the highest number, and some prodrugs such as valaciclovir and valganciclovir are clinically available. ATP-binding cassette efflux transporter, P-glycoprotein (P-gp), reduces the intestinal absorption of lipophilic P-gp substrate drugs, and SLC transporter-targeted prodrugs of P-gp substrate drugs circumvented the P-gp-mediated efflux transport. Thus, SLC transporter-targeted prodrug derivatization seems to be feasible approach to increase the oral bioavailability by overcoming various unwanted physicochemical properties of orally administered drugs, although the effect of food on prodrug absorption should be taken into consideration.

Biphasic and boundary lubrication mechanisms in artificial hydrogel cartilage: A review.

Various studies on the application of artificial hydrogel cartilage to cartilage substitutes and artificial joints have been conducted. It is expected in clinical application of artificial hydrogel cartilage that not only soft-elastohydrodynamic lubrication but biphasic, hydration, gel-film and boundary lubrication mechanisms will be effective to sustain extremely low friction and minimal wear in daily activities similar to healthy natural synovial joints with adaptive multimode lubrication. In this review article, the effectiveness of biphasic lubrication and boundary lubrication in hydrogels in thin film condition is focused in relation to the structures and properties of hydrogels. As examples, the tribological behaviors in three kinds of poly(vinyl alcohol) hydrogels with high water content are compared, and the importance of lubrication mechanism in biomimetic artificial hydrogel cartilage is discussed to extend the durability of cartilage substitute.