Sprague-Dawley (SD) rats are broadly used in preclinical studies for drug development, so a lot of information for the rats can be obtained especially from pharmacokinetic, pharmacological and toxicological studies. The purpose of this study was to clarify whether SD rat skin can be used to predict human skin permeability. In vitro permeation studies of the three model drugs, nicorandil, isosorbide dinitrate, and flurbiprofen, through human skin and SD rat skin were performed using Franz-type diffusion cells. The permeation rates of the three model drugs through human skin and SD rat skin were determined, and their variations were evaluated. The inter-individual variations in SD rat skin permeability of the three model drugs were much lower than that in human skin permeability, although the permeation rates of the three model drugs through the SD rat skin were about twice those through human skin. In addition, no difference in the skin permeability coefficients of the three model drugs was obtained between fresh SD rat skin and frozen SD rat skin. The markedly smaller variation in the permeability through SD rat skin compared with that through human skin indicated that in vitro permeation studies using SD rat skin would be especially useful for evaluating differences in the skin permeability of the three model drugs as well as for predicting human skin permeability.

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Atazanavir (ATV) is a low oral bioavailability (BA) compound and, clinically, is generally coadministrated with ritonavir (RTV), which boosts the oral BA of ATV by inhibiting cytochrome P450 (CYP) 3A, and P-glycoprotein (Pgp) via the same metabolic pathway. However, depending on pharmacokinetic interaction, RTV-boosted ATV has great potential for other comedication. In this study we demonstrated the pharmaceutical approach to BA improvement of ATV without RTV in rats, based on the solid dispersion system using sodium lauryl sulfate (SLS) as a carrier and Gelucire 50/13 as an absorption enhancer. ATV solid dispersions in SLS were prepared by a conventional solvent method and, at ratios of ATV to SLS of 1 : 2 and 1 : 3, were demonstrated to form an amorphous state in powder X-ray diffraction (PXRD) analysis and exhibited 2.26- and 2.36-fold improvement in a dissolution test in comparison to bulk ATV, respectively. After oral administration to rats, ATV solid dispersion in SLS at a ratio of 1 : 2 showed a 3.5-fold increase in BA compared with bulk ATV. Moreover, the addition of Gelucire 50/13 to ATV solid dispersion, at a total ratio of Gelucire 50/13, ATV and SLS 1 : 1 : 2 gave 7.0- and 4.7-fold increase in Cmax and BA compared with bulk ATV, respectively, when the relative BA to RTV-boosted ATV reached 93%. The results in this study proved that a pharmaceutical approach could improve the bioavailability of ATV without pharmacokinetic interaction with RTV.

Animal skins are frequently used as an alternative to human skin in percutaneous absorption studies, because human skin is not always available and the use of human tissues and organs creates ethical problems. In addition, a large variation has been found among human skin specimens as a result of differences in gender, age, race and anatomical donor site. [1][2][3][4][5][6][7][8][9][10] Numerous animal models, including primate, porcine, mouse, rat, guinea pig and snake, have been utilized for skin permeability studies. 1,3,4,[11][12][13] Animal skins with a small variation in skin permeability may be much better than human skin for determining or estimating the skin permeability of drugs and for developing transdermal formulations. 1,14,15) In our earlier study, 16) we investigated the in vitro permeation studies of the three model drugs, nicorandil (NR), isosorbide dinitrate (ISDN) and flurbiprofen (FP), through human abdominal skin (human skin) and Sprague-Dawley rat dorsal skin (SD rat skin) were performed using Franz-type diffusion cells. The three model drugs were selected because of their different log K ow (logarithm of octanol/water partition coefficient at 37°C) (Table 1). NR, ISDN and FP were used as hydrophilic, lipophilic and highly lipophilic drugs, respectively. The permeation rates of the three model drugs were determined, and their variations were evaluated. The inter-individual variations in human skin permeability for each model drug were larger than the intra-individual variations in human skin permeability. Although the interindividual variations in SD rat skin permeability for each model drug were much lower than those in human skin permeability, and the permeation rates of those drugs through the SD rat skin were approximately twice that through human skin.16) The markedly smaller variation in the permeability through SD rat skin compared with that through human skin indicated that the in vitro permeation studies using SD rat skin would be particularly useful for evaluating differences in the skin permeability of the three model drugs as well as for predicting human skin permeability. Recently, pig skin has been frequently used for skin permeation studies. 1,[17][18][19][20][21][22] It has been reported that the histological characteristics and permeability properties of pig skin closely resemble those of human skin. 6,7,[23][24][25][26][27][28] In addition, the Yucatan micropig (YMP) has been utilized for numerous research applications and has been suggested as an animal The purpose of this study was to evaluate the variations in the in vitro Yucatan micropig (YMP) skin permeabilities of drugs and to clarify whether YMP skin can be used to predict human skin permeability. In vitro permeation studies of the three model drugs, nicorandil, isosorbide dinitrate and flurbiprofen, through YMP skin were performed using Franz-type diffusion cells. The permeation rates of the three model drugs were determined, and their variations were evaluated. The inter-individual variations in YMP skin permeab...

The use of highly active antiretroviral therapy (HAART) has resulted in significant reductions in human immunodeficiency virus (HIV)-related mortality and morbidity, and transformed HIV disease to a chronic syndrome.1,2) Despite improved clinical outcomes with protease inhibitor (PI)-based HAART regimens, there are still many problems, such as high pill burden, resistance to antiretrovirals and metabolic abnormalities (e.g., hyperlipidemia, hyperglycemia). [3][4][5] Moreover, the transformation of HIV disease to a chronic syndrome also practically means that once patients start HAART, they should receive the drugs included in the HAART regimen for the rest of their life; therefore, not only long-term efficacy but also the safety of these drugs are of clinical significance.Atazanavir (ATV) is an azapeptide compound and the seventh addition to the family of HIV PIs. ATV may have an advantage over other PIs because of once-daily dosing, a distinct resistance profile, and a lack of insulin resistance and lipid increase.6,7) With these advantages, ATV has been successfully used in treatment-native and -experienced HIV patients.8) Similar to other PIs, however, ATV is poorly watersoluble and is known as a substrate of both a hepatic metabolizing enzyme, cytochrome P450 (CYP) 3A, and an intestinal drug efflux pump, P-glycoprotein (Pgp), thus resulting in low oral bioavailability (BA). 9) Clinically, to resolve this disadvantage, ATV is generally used with low-dose ritonavir (RTV) in the HAART regimen. RTV is also classified as a PI and is well known as a potent inhibitor of both CYP3A and Pgp. With this potent inhibition property, low-dose RTV has been demonstrated clinically to boost the BA of another concomitant PI. [10][11][12] HIV patients are typically treated with multiple drugs in addition to their HAART regimen. Hence, based on pharmacokinetic interaction, RTV-boosted HAART has great potential for drug-drug interactions with CYP3A and Pgp. 13,14) Moreover, it was also reported that RTV is not only a potent inhibitor but also a potent inducer of CYP3A and Pgp with chronic use. 15,16) This contradictory characteristic of RTV would further complicate drug-drug interactions and facilitate the clinical difficulties of HIV patients whose HIV infection must be controlled by RTV-boosted HAART. In addition, there are few studies on the effect of chronic use of lowdose RTV on its boosting effect and on pharmacokinetic interactions with concomitant drugs in addition to the HARRT regimen.We previously reported that the ATV pharmaceutical formulation, the physical mixture of Gelucire 50/13 and ATV solid dispersion in sodium lauryl sulfate (ATV-SLS SDϩG), could improve the BA of ATV without pharmacokinetic interaction with RTV.17) The aim of this study was to investigate the long-term efficacy and safety of RTV-boosted ATV and ATV-SLS SDϩG and to directly compare both formulations; therefore, we administered RTV-boosted ATV or ATV-SLS SDϩG for 14 d to rats and compared the pharmacoki- Atazanavir (ATV) is clinically coadminis...