Tetsuya Aiba

Poor Correlation Between Intestinal and Hepatic Metabolic Rates of CYP3A4 Substrates in Rats

AbstractPurpose. To clarify the contribution of the intestinal first-pass metabolism to the drug bioavailability, the correlation between the intestinal and hepatic metabolism of human CYP3A4 substrates was investigated in rats. Methods. The metabolic rates of four compounds (lidocaine, quinidine, nifedidpine, and rifabutin) were examined with excised intestinal tissues and liver microsomes. The intestinal and hepatic expression of CYP3A1/23 and CYP3A2 was evaluated by Western blot analysis. Results. Rifabutin was metabolized fastest, and lidocaine was metabolized slowest in excised intestinal tissues. By contrast, lidocaine was metabolized fastest and rifabutin was the slowest in liver microsomes. The hepatic metabolism of lidocaine was inhibited by a CYP2D6 substrate desipramine, not by a CYP3A4 inhibitor ketoconazole. In addition, members of the CYP3A subfamily expressed in the intestine were different from those expressed in the liver. Conclusions. Poor correlation between the intestinal and hepatic metabolism of human CYP3A4 substrates in rats may be caused by the contribution of the CYP2D subfamily to the drug metabolisms in the liver and also by the unique expression of the CYP3A subfamily in the intestine.

Population Pharmacokinetic Analysis of Vancomycin Using Serum Cystatin C as a Marker of Renal Function

ABSTRACT We determined the population pharmacokinetics of vancomycin (VAN) using the glomerular filtration rate (GFR) estimated from the serum cystatin C concentration. We examined the predictive performance of the trough serum VAN concentration for determination of the initial dose by using a new model for the analysis of the population pharmacokinetic parameters. Data for 86 patients were used to estimate the values of the population pharmacokinetic parameters. Analysis with a nonlinear mixed-effects modeling program was done by using a one-compartment model. Data for 78 patients were used to evaluate the predictive performance of the new model for the analysis of population pharmacokinetic parameters. The estimated GFR values determined by using Hoeks formula correlated linearly with VAN clearance (VAN clearance [ml/min] = 0.825 × GFR). The mean volume of distribution was 0.864 (liters/kg). The interindividual variability of VAN clearance was 19.8%. The accuracy of the prediction determined by use of the new model was statistically better than that determined by use of the Japanese nomogram-based model because the 95% confidence interval (−3.45 to −1.38) of the difference in each value of the mean absolute error (−2.41) did not include 0. Use of the serum cystatin C concentration as a marker of renal function for prediction of serum VAN concentrations may be useful.

Effect of pH on the skin permeability of a zwitterionic drug, cephalexin

Abstract Skin permeability of the zwitterionic drug, cephalexin, was measured at various pH. A U-shaped curve was obtained for the relationship between the permeability coefficient and pH. Although cephalexin degraded dependent on the pH, the concentration in the suspended donor solution was maintained constant by the high dissolution rate. The barrier function of skin, which was assessed by the permeation of the nonelectrolytes, cortisone and o-mannitol, did not change over the range from pH 3.0 to 7.0. The permeability coefficient of cephalexin decreased with increase in zwitterion fraction and decrease in fractions of cation and anion, suggesting that each ionic species has different skin permeability. The permeability coefficient of zwitterion, estimated on this assumption of each ionic species having different permeability, was about 10% that of cation and anion. The octanol/buffer distribution coefficient and diffusion coefficient were also lower for zwitterion than for cation and anion. This suggests that the pH dependency in skin permeability of cephalexin may reflect the permselective property of skin dependent on the lipophilicity and/or diffusivity of ionic species.

Characterization of non-linear relationship between total and unbound serum concentrations of valproic acid in epileptic children

Objective:  To establish a regression equation to properly estimate the unbound serum concentration of valproic acid (VPA) from its total serum concentration; the relationship between total and unbound serum VPA concentrations was retrospectively characterized.

The increased intestinal absorption rate is responsible for the reduced hepatic first‐pass extraction of propranolol in rats with cisplatin‐induced renal dysfunction

The mechanisms responsible for the increased bioavailability of propranolol in renal dysfunction were investigated in rats. Experimental acute renal failure (ARF) was induced by intraperitoneal injection of cisplatin (5 mg kg−1). ARF induced a significant increase in blood propranolol concentration after intra‐intestinal administration. The extent of bioavailability (F) of propranolol at an intestinal dose of 15 mg kg−1 was 16.4% and 26.9% in control and ARF rats, respectively, and the F value at a 37.5 mg kg−1 dose was 54.7% and 81.4% in control and ARF rats, respectively. In contrast, the blood propranolol concentration following intraportal infusion was not increased significantly in ARF rats. The hepatic first‐pass extraction (Eh) was dose‐dependent and saturable: Eh of propranolol in control rats was 58.0% and 18.3% at 8 and 20 mg kg−1, respectively, and Eh in ARF rats was 50.8% and 19.9% at 8 and 20 mg kg−1, respectively. The initial absorption rate of propranolol from the intestine in ARF rats was significantly greater compared with control rats. These results indicated that the increased bioavailability of propranolol in rats with cisplatin‐induced renal dysfunction was mainly a result of the increased absorption rate in the intestine followed by the partial saturation of hepatic first‐pass metabolism.

A study of the hydrophilic cellulose matrix: Effect of indomethacin and a water-soluble additive on swelling properties

A swelling measurement device was designed to observe the axial swelling direction of a matrix containing various types of hydrophilic cellulose derivatives (methylcellulose, hydroxypropylmethylcellulose and hydroxypropylcellulose). The effect of indomethacin and lactose on the swelling properties was also studied. The maximum swelling index and the apparent diffusion coefficient of water in the matrix, calculated from the swelling data, were used to describe the swelling properties of the matrix, reflecting the matrix integrity. The results showed that hydroxypropylcellulose produced a matrix with a high integrity. Indomethacin and lactose changed the swelling properties of the hydrophilic cellulose matrices in this study.

In vivo application of chitosan to improve bioavailability of cyanocobalamin, a form of vitamin B12, following intraintestinal administration in rats.

The effect of chitosan on the intestinal absorption of cyanocobalamin (VB12), a stable form of vitamin B12, was investigated in vivo in rats, with the aim of improving the oral bioavailability of VB12 for anemia treatment in patients with gastrectomy. The bioavailability was evaluated based on the plasma concentration profile of VB12 following intraintestinal administration of the VB12 solution containing chitosan at various concentrations. The bioavailability of VB12 was 0.6±0.2% when the chitosan-free VB12 solution was administered, while it increased to 10.5±3.3% when chitosan was dissolved in the VB12 solution at a concentration of 1%. The bioavailability of VB12 increases with the chitosan concentration, in which chitosan seems to augment the amount of VB12 absorbed without affecting the absorption rate constant of VB12. It was also shown that the bioavailability of VB12 does not increase further when the degree of chitosan deacetylation is increased from 83 to 100% by substitutively employing the fully deacetylated chitosan. These findings suggest that the oral administration of VB12 with readily available chitosan may be a practical approach for anemia treatment in patients with gastrectomy.

Comparative study on altered hepatic metabolism of CYP3A substrates in rats with glycerol-induced acute renal failure.

To examine the mechanism accounting for the diverse alteration of hepatic metabolism of CYP3A substrates observed with renal function being severely impaired, the hepatic drug metabolizing activity was evaluated using liver microsomes prepared from rats with glycerol‐induced acute renal failure (ARF). Midazolam, nifedipine and rifabutin were employed as representative CYP3A substrates. When the Michaelis‐Menten parameters, Km and Vmax, were examined in the incubation study, the Km values of midazolam and nifedipine in ARF rats were shown to decrease by 50.9% and 29.9% compared with the normal value, respectively. The Vmax values of midazolam and nifedipine in ARF rats also decreased by 49.3% and 28.0%, respectively, showing that their decreased Km values accompanied the decreased Vmax values. The parameters of nifedipine seemed to alter to a lesser extent than those of midazolam. As for rifabutin metabolism, the decrease in the Km value was observed in ARF rats, but it did not accompany the decrease in the Vmax value. Then, the hepatic expressions of the CYP3A subfamily were examined with western blotting using anti‐CYP3A1 and anti‐CYP3A2 antibodies. It was revealed that the hepatic expression of CYP3A2 decreased, while that of CYP3A1 was unaffected. Additionally, a band signal deduced to originate from CYP3A9 was clearly detected in ARF, but not in normal rats. Considering each substrate having different specificities for CYP3A subfamily member proteins, individual alterations of hepatic CYP3A subfamily expression seem to underlie the diverse alterations of hepatic metabolism of CYP3A substrates in ARF rats. Copyright

Effect of experimental renal dysfunction on bioavailability of ajmaline in rats

The effect of renal dysfunction on the bioavailability of ajmaline has been investigated in rats, where experimental renal dysfunction was induced by subcutaneous injection of uranyl nitrate (10 mg kg−1). Renal dysfunction did not cause any change in the blood ajmaline concentration after intravenous administration (2 mg kg−1), but it increased the blood ajmaline concentration by approximately 2.8‐fold after intraduodenal administration (10 mg kg−1). The availability of ajmaline in control rats was 16.7%, whereas the availability was increased to 41.1% in rats with renal dysfunction. The unbound fraction in the blood and the metabolic activity in the liver, was assessed with the 10000‐g supernatant fraction and with isolated hepatocytes, respectively. The values were found to be similar in both groups. The blood concentration following intraportal infusion was only slightly increased in rats with renal dysfunction, but the hepatic first‐pass extraction was infusion rate‐dependent and saturable. The initial absorption rate of ajmaline from the small intestine in rats with renal dysfunction was significantly greater compared with control rats. These results indicated that the increased availability of ajmaline in renal dysfunction was mainly a result of partially saturated extraction in the liver, which was caused by an increased absorption rate in the intestine and non‐linear extraction in the liver.

Pharmaceutical properties of a low-substituted hydroxypropyl cellulose (L-HPC) hydrogel as a novel external dressing

Controlling the moisture balance between exudates and their transpiration from the surface of wounded skin is important for healing. Low-substituted hydroxypropyl cellulose (L-HPC) hydrogel sheets (HGSs) possessing high water retention and water vapor transmission properties were prepared by neutralizing the highly viscous alkaline liquid of 7-10% L-HPC. Glycerol-impregnated L-HPC hydrogel sheets (L-HPC G-HGSs) were obtained by exchanging aqueous liquid in L-HPC HGSs. The physical characteristics required for wound dressings, i.e., mechanical strength, adhesive strength, and water retention properties, as well as the water vapor transmission (WVT) properties of L-HPC HGSs and L-HPC G-HGSs were evaluated. The mechanical strengths of L-HPC HGSs were enhanced with increases in the L-HPC content. The impregnation of glycerol in L-HPC HGSs yielded a significantly elasticated sheet. The adhesive strengths of L-HPC HGSs were significantly lower than those of commercial medical dressings. Water retention in L-HPC HGSs after being stored for 2h at 37°C was approximately 50%. The WVT rate of 7% L-HPC HGS was approximately 40g/m(2)/h, which was markedly higher than that of silicone gel type medical dressings. In conclusion, L-HPC HGSs are promising dressings that maintain an adequate moisture balance by transpiring excessive wound exudates with less damage to the healing wound.