Incomplete Oral Bioavailability Research Articles

Optimization of a Cefuroxime Axetil-Loaded Liquid Self-Nanoemulsifying Drug Delivery System: Enhanced Solubility, Dissolution and Caco-2 Cell Uptake.

Cefuroxime axetil (CA) is an oral cephalosporin which hydrolyzes rapidly to the active parent compound cefuroxime. CA is known to have incomplete oral bioavailability (30–50%) due to its poor solubility and enzymatic conversion to cefuroxime in the gut lumen. In order to overcome these drawbacks, a lipid-based self-nanoemulsifying drug delivery system (SNEDDS) has been developed and optimized. The SNEDDS formulations were prepared using the aqueous phase titration method. The greatest self-emulsifying area was found in the 2:1 Smix ratio. As a result, different SNEDDS formulations were carefully selected from this phase diagram based on their smaller droplet size < 100 nm, polydispersity index ≤ 0.5, dispersibility (Grade A), and transmittance (%) > 85%. Thermodynamic stability tests were carried out in order to rule out any metastable/unstable SNEDDS formulations. The droplet size, polydispersity index, zeta potential, and entrapment efficiency (% EE) of optimized CA-loaded SNEDDS (C-3) were 18.50 ± 1.83 nm, 0.064 ± 0.008, −22.12 ± 1.20 mV, and 97.62 ± 1.06%, respectively. In vitro release studies revealed that the SNEDDS formulation had increased CA solubility. CA-SNEDDS-C3 increased CA cellular uptake, possibly due to increased CA solubility and the inhibition of enzymatic conversion to cefuroxime. Finally, in terms of the improvement of oral bioavailability, CA-loaded-SNEDDS could be a viable alternative to commercially available CA formulations.

Redispersible lipid nanoparticles of Spironolactone obtained by three drying methods

This work aimed to prepare a pediatric formulation for Spironolactone a poor water soluble drug characterized by incomplete oral bioavailability, bitter taste, and tendency to destabilize in aqueous media. Regarding to the good solubility of Spironolactone in lipid materials, lipid nanoparticles seemed to be an excellent way to overcome these issues. In an attempt to prevent eventual stability problems linked to lipid nanoparticles, we dried the prepared nanosuspensions into redispersible powder, in association with pediatric adapted drying carriers. A comparison study between drying methods have been conducted. Fluid Bed Drying was introduced as a novel method of drying lipid nanoparticles. This method was compared to usual methods; freeze drying and spray drying. The comparison took into account quality of the obtained powder and its redispersibility, palatability, drug stability during the process and the effect of the drying method on particle size, entrapment efficiency and dissolution behavior of Spironolactone. The obtained preparations showed size increase of nanoparticles, significant differences about chemical stability and dissolution behavior of same formulas dried with different techniques have been noticed. Thanks to excellent entrapment of drug substance into nanoparticles, the extemporaneous prepared nanosuspensions exhibited a palatable sweaty taste adapted to the needs of pediatric patients.

Concentration and pH dependency of alpha-methyldopa absorption in rat intestine.

The intestinal absorption of alpha-methyldopa from perfused segments of rat intestine was determined. Jejunal and ileal segments were studied at pH 4.5, 6.0 and 7.4 at an alpha-methyldopa concentration of 0.01 mM, and at pH 6.0 at concentrations of 0.01, 0.10 and 10 mM. Intestinal absorption was found to depend on both concentration and pH but not on segment. A weak positive correlation (r = 0.5) was observed between net water absorption and alpha-methyldopa absorption, similar to that observed for amino acids. The low intestinal wall permeability of alpha-methyldopa under normal intestinal pH conditions (pH 7.4) is consistent with the incomplete oral bioavailability of this drug.

Preclinical pharmacokinetics and in vitro metabolism of dasatinib (BMS-354825): a potent oral multi-targeted kinase inhibitor against SRC and BCR-ABL

Dasatinib (BMS-354825), a potent oral multi-targeted kinase inhibitor against SRC and BCR-ABL, has recently been approved for the treatment of chronic myelogenous leukaemia (CML) in imatinib-acquired resistance and intolerance. In vitro and in vivo studies were conducted to characterize the pharmacokinetics and metabolism of dasatinib in mouse, rat, dog, and monkey. Possible mechanisms contributing to the incomplete oral bioavailability of dasatinib in animals were investigated. Metabolic stability of dasatinib was measured after incubation with liver microsomes (either NADPH- or UDPGA-fortified) and isolated hepatocytes obtained from mouse, rat, dog, monkey, and human. In all cases, substrate depletion over time was measured, and appropriate scaling factors were used to predict in vivo clearance. Pharmacokinetics of dasatinib were determined in mice, rats, dogs, and monkeys after administration of single intravenous or oral doses. In addition, the routes of excretion were investigated after administration of dasatinib to bile duct cannulated (BDC) rats. Absorption and first-pass metabolism were evaluated as possible reasons for the incomplete oral bioavailability using various in vitro and in vivo models like Caco-2 cells, P-glycoprotein (P-gp) knockout mice, and intra-portal dosing in rats. In vivo systemic plasma clearance values of dasatinib were 62, 26, 25, and 34 ml/min/kg in mouse, rat, dog, and monkey, respectively. Scaling of in vitro hepatocyte and liver microsomal data gave reasonably good predictions of in vivo clearances across all species. Percent distribution in blood cells ranged from 43% in mouse to 57% in dog. Dasatinib showed high volumes of distribution (>3 l/kg) and high serum protein binding values (>90%) in all four species tested. Oral bioavailability of dasatinib ranged from 14% in the mouse to 34% in the dog. In rats, bioavailability after an intraportal dose was comparable to that after intra-arterial administration. In BDC rats, less than 15% of an intravenous dose was excreted unchanged in urine, bile, and the gastrointestinal tract, suggesting that dasatinib is cleared primarily via metabolism. Dasatinib has high intrinsic permeability in Caco-2 cells, however, the efflux ratio was approximately two-fold indicating that it may be a substrate for an intestinal efflux transporter. However, in vivo studies in P-gp knockout mice versus wild-type mice showed no difference in the amount of dasatinib remaining unabsorbed in the gastrointestinal tract, suggesting that P-gp may not be responsible for the incomplete bioavailability. Dasatinib shows intermediate clearance in mouse, rat, dog, and monkey, and distributes extensively in those species. Oxidative metabolism appears to be the predominant clearance pathway. The incomplete oral bioavailability may be due to both incomplete absorption and high first-pass metabolism. However, the efflux transporter, P-glycoprotein does not appear to be limiting oral absorption.

P-glycoprotein plays a role in the oral absorption of BMS-387032, a potent cyclin-dependent kinase 2 inhibitor, in rats.

BMS-387032, a novel cyclin-dependent kinase 2 inhibitor, is currently in phase I clinical trials for anticancer therapy. The oral bioavailability of BMS-387032 has been found to be about 31% in rats. Absorption and first-pass metabolism were evaluated as possible reasons for the incomplete oral bioavailability in rats. Male Sprague-Dawley rats were given single doses of BMS-387032 intraarterially (9.1 mg/kg), orally (9.1 mg/kg), or intraportally (10 mg/kg). The routes of excretion of BMS-387032 after intravenous dosing were investigated in bile-duct-cannulated rats. The rate of metabolism of BMS-387032 was investigated in liver microsomes. The permeability of BMS-387032 was evaluated using Caco-2 cells, an in vitro model of the intestinal epithelium. To determine if BMS-387032 was a P-glycoprotein substrate, brain uptake studies were conducted in P-glycoprotein knockout versus wildtype mice. The exposure in rats after an intraportal dose was similar to that after an intraarterial dose, indicating that absorption may play a greater role than liver first-pass metabolism in the low oral bioavailability seen in rats. After an intravenous dose, the percent of dose excreted unchanged in the urine and bile over a 9-h period was 28% and 11%, respectively. In vitro studies in rat liver microsomes showed low rates of metabolism of BMS-387032. The Caco-2 cell permeability of BMS-387032 was <15 nm/s in the apical to basolateral direction, and 161 nm/s in the basolateral to apical direction, indicating that it may be a substrate for an intestinal efflux transporter. A P-glycoprotein binding assay showed that BMS-387032 might be a P-glycoprotein modulator. Brain penetration studies in mice showed brain levels of BMS-387032 about 3.5-fold higher in P-glycoprotein knockout mice than in wildtype mice, providing evidence of BMS-387032 being a P-glycoprotein substrate. Poor absorption may be playing a greater role than extensive first-pass metabolism in the incomplete oral bioavailability of BMS-387032 seen in rats. The efflux transporter, P-glycoprotein, may be responsible for limiting absorption, as BMS-387032 appears to be a substrate of P-glycoprotein.

Pharmacokinetic evaluation of 3'-azido-2', 3'-dideoxyuridine-5'-O-valinate-hydrochloride as a prodrug of the anti-HIV nucleoside 3'-azido-2', 3'-dideoxyuridine.

3'-Azido-2', 3'-dideoxyuridine (AZDU, AzddU, CS-87) has been shown to have potent anti-HIV activity in vitro. However, the compound exhibits a relatively short half-life and incomplete oral bioavailability in humans. In an effort to improve the pharmacokinetic properties of AZDU, prodrug 3'-azido-2',3'-dideoxyuridine-5'-O-valinate hydrochloride (AZDU-VAL) was synthesized by the esterification of 5'-OH function in AZDU. The objective of this study was to investigate the biotransformation and pharmacokinetics of AZDU-VAL along with its antiviral parent compound AZDU following intravenous and oral administration to rats. Adult male Sprague-Dawley rats were administered AZDU or AZDU-VAL by intravenous injection or oral gavage. Concentrations of AZDU-VAL and AZDU were determined by HPLC. Pharmacokinetic parameters were generated by area-moment analysis. The bioavailability of AZDU after oral administration was approximately 53%. The terminal phase half-life of the nucleoside analogue ranged between 0.6 h after intravenous administration and 1 h following oral administration. In vivo the prodrug was rapidly and efficiently biotransformed to yield AZDU following intravenous and oral administration. The apparent availability of AZDU was virtually complete following oral administration of prodrug AZDU-VAL averaging 101%. The bioavailability of AZDU following intravenous administration of AZDU-VAL averaged 106%. In summary, the disposition of AZDU was dose dependent over the dose range of 25-100 mg/kg. Renal clearance and steady state volume of distribution were lower at the higher dose level. Prodrug AZDU-VAL demonstrated improved oral bioavailability as evidenced by complete absorption and efficient bioconversion to AZDU. The results suggest that AZDU-VAL may be a promising prodrug for the delivery of AZDU.

Intestinal secretion of intravenous talinolol is inhibited by luminal R-verapamil.

To examine the secretion of the beta1-adrenergic receptor antagonist talinolol into the small intestine during its intravenous administration and to show the relevance of the P-glycoprotein-modulating drug verapamil for this secretory transport mechanism in humans. In six healthy volunteers the intestinal steady-state perfusion technique (triple lumen tubing system) was used for measuring the appearance of talinolol within the small intestine while the drug was infused intravenously. During four of the seven perfusions performed, the perfusion fluid was changed from a verapamil-free solution and talinolol appearance was measured while a R-verapamil-containing solution (565 micromol/L) was perfused. Talinolol was transported into the intestinal lumen up to a concentration gradient between lumen and blood of about 5.5:1. While perfusing the small intestine with a verapamil-free solution, the intestinal secretion rate of talinolol ranged from 1.94 to 6.62 microg/min per 30 cm length of the intestine (median values). Perfusion of a R-verapamil-containing perfusion fluid resulted in lower secretion rates (0.59 to 3.71 microg/30 cm x min), corresponding to 29% to 56% of the values obtained without verapamil supplied intraluminally. Intravenously administered talinolol is actively secreted into the human small intestine. This secretion is reduced by the intraluminal supply of the P-glycoprotein modulating drug R-verapamil. This gives further rationale for P-glycoprotein-mediated intestinal drug secretion as a cause for incomplete oral bioavailability and for drug interactions during intestinal absorption.

Improved dissolution and bioavailability of phenytoin by sulfobutylether- β-cyclodextrin ((SBE) 7m- β-CD) and hydroxypropyl- β-cyclodextrin (HP- β-CD) complexation

The inclusion complexation of phenytoin with charged and neutral water-soluble cyclodextrins (CDs), (SBE) 7m- β-CD and HP- β-CD, was studied in order to improve the low aqueous solubility and incomplete oral bioavailability of phenytoin. Effects of CDs on the aqueous solubility of phenytoin were determined by phase-solubility method at pH 7.4 and 11.0. Solubility of phenytoin increased as a function of CD concentration, showing A L type diagrams for both (SBE) 7m- β-CD and HP- β-CD which indicate a formation of 1:1-complexes. Solid inclusion complexes of phenytoin with (SBE) 7m- β-CD and HP- β-CD were prepared by freeze-drying. Dissolution rate of phenytoin was increased with inclusion complexes as well as with phenytoin/HP- β-CD physical mixture in vitro. Also the freeze-drying of phenytoin tended to enhance the dissolution of phenytoin in vitro. However, plain phenytoin (300.0 mg) pharmacokinetics after oral administration as a crystal form and as a freeze-dried form were comparable in dogs. CD-based formulations of phenytoin increased peak plasma concentration of phenytoin about 1.6-fold and bioavailability (AUC 0–24 h) of phenytoin about 2-fold compared to plain phenytoin. Oral pharmacokinetics were not statistically different among various CD formulations. This study indicates that increased bioavailability of phenytoin in the presence of CDs was due to an increased extent of drug dissolution.

Yohimbine bioavailability in humans

Pharmacokinetic profiles were determined in seven healthy young male subjects following single oral and intravenous doses of 10 mg of yohimbine hydrochloride. The drug was rapidly eliminated (t1/2 beta 0.58 h orally and t1/2 beta 0.68 h intravenously). Following intravenous administration the data fit a two-compartment pharmacokinetic model, with a very rapid distribution phase (t1/2a was approximately 6 min). Both the oral and the intravenous yohimbine clearance values were high but oral clearance values were much higher (mean 9.77 ml.min-1.kg-1 intravenous versus 55.9 ml.min-1.kg-1 oral). The oral bioavailability showed great variability, ranging from 7% to 87% (mean value was 33%). The incomplete oral bioavailability of yohimbine may reflect either incomplete absorption from the gastrointestinal tract or an hepatic first pass effect. Although yohimbine is rapidly absorbed when given orally, the bioavailability is quite variable and considerable individualization of dosing may be necessary when the drug is used orally for clinical indications.

Pharmacokinetic Relationships Between Cinromide and Its Metabolites in the Rhesus Monkey I: 3-Bromocinnamamide, an Active Metabolite

Fifty percent of a cinromide dose was metabolized to an active metabolite in the rhesus monkey. The steady-state concentration of this metabolite was 3-6 times that of the parent drug, depending on the route of administration. Cinromide is a medium-extraction ratio drug with a short half-life (0.92±0.23hr) when compared with the active metabolite, which has a low extraction ratio and a longer half-life (4.43±0.76hr). Incomplete oral bioavailability of cinromide is a result of first-pass metabolism rather than incomplete absorption.