mRNA expression levels of cytochrome P450 CYP1A2, CYP3A4, and CYP3A5 in the epidermis: a focus on individual differences among Japanese individuals.

Various cytochrome P450 enzymes (CYPs) that contribute to drug metabolism are expressed in the skin. However, variation among individuals in CYP expression profiles is not well-understood.To investigate CYPs related to the metabolism of transdermal preparations in Japan, multiple skin tissue specimens of individuals of Japanese descent were prepared, and the mRNA expression levels of CYP1A2, CYP3A4, and CYP3A5 were measured. Associations between the expression patterns of these CYPs and body mass index (BMI) were also investigated.There were considerable individual differences in epidermal CYP1A2 mRNA expression levels, and CYP1A2 showed a weak positive correlation with CYP3A4 mRNA expression levels. In contrast to previous results for other organs, epidermal CYP3A4 mRNA expression levels showed a weak positive correlation with BMI.CYP3A4 in the epidermis may have been locally enhanced as a defence mechanism against xenobiotics in response to impaired barrier function. These differences in mRNA expression in the skin may affect the transdermal absorption of drugs, such as lidocaine and fentanyl, which are metabolised by multiple overlapping CYPs.Our study provides new insights into drug metabolism in the skin. These results are valuable for predicting drug effects and transdermal drug transfer rates in Japanese patients.

Transdermal pilocarpine on the skin over salivary glands to increase salivation: an in vivo study.

BACKGROUND: Hyposalivation is treated using oral cholinergic drugs; however, systemic side effects occasionally lead to discontinuation of treatment. We aimed to investigate the effects of transdermal pilocarpine on the salivary gland skin on saliva secretion and safety in rats. METHODS: Pilocarpine was administered to rats orally (0.5 mg/kg) or topically on the salivary gland skin (5 mg/body). Saliva volume, the number of sweat dots, and fecal weight were measured along with pilocarpine concentration in plasma and submandibular gland tissues. RESULTS: Saliva volume significantly increased 0.5 h after oral administration and 0.5, 3, and 12 h after topical administration. Fecal weight and sweat dots increased significantly 1 h after oral administration; however, no changes were observed after topical application. The pilocarpine concentration in the submandibular gland tissues of the topical group was higher than that in the oral group at 0.5, 3, and 12 h of administration. CONCLUSIONS: Pilocarpine application to salivary gland skin persistently increased salivary volume in rats without inducing sweating or diarrhea. Transdermal pilocarpine applied to the skin over the salivary glands may be an effective and safe treatment option for hyposalivation.

Sodium citrate buffer improves pazopanib solubility and absorption in gastric acid-suppressed rat model.

Pazopanib exhibits pH-dependent solubility and its absorption depends primarily on the stomach pH. Significant decrease of pazopanib absorption by coadministration with proton pump inhibitors in clinical situation need to be overcome. Thus, the purpose of this study is firstly to investigate the effect of acidic beverages and sodium citrate buffer on the solubility of pazopanib and secondly to examine the effect of sodium citrate buffer on pazopanib absorption in a rat model with esomeprazole-mediated gastric acid suppression. Pazopanib solubility decreased with increasing pH of sodium citrate buffer in vitro. Interestingly, its solubility in some acidic beverages was significantly lower than that in sodium citrate buffer of the same pH. The AUC0-24h of pazopanib administered in tap water to rats treated with esomeprazole (ESP rats) was 66 % lower than that in the control rats treated with saline. However, AUC0-24h was 4.8 times higher in ESP rats that received pazopanib with sodium citrate buffer (pH 2.3) compared to ESP rats that received pazopanib with tap water. Our results indicate that the drug-drug interactions between pazopanib and proton pump inhibitors can be overcome, at least in part, by suspending pazopanib in sodium citrate buffer.

Validation of an automated sample preparation module directly connected to LC-MS/MS (CLAM-LC-MS/MS system) and comparison with conventional immunoassays for quantitation of tacrolimus and cyclosporin A in a clinical setting.

BACKGROUND: Therapeutic drug monitoring (TDM) systems generally use either liquid chromatography/tandem mass spectrometry (LC-MS/MS) or immunoassay, though both methodologies have disadvantages. In this study, we aimed to evaluate whether a CLAM-LC-MS/MS system, which consists of a sample preparation module directly connected to LC-MS/MS, could be used for clinical TDM work for immunosuppressive drugs in whole blood, which requires a hemolytic process. For this purpose, we prospectively validated this system for clinical measurement of tacrolimus and cyclosporin A in patients' whole blood. The results were also compared with those of commercial immunoassays. METHODS: Whole blood from patients treated with tacrolimus or cyclosporin A at the Department of Nephrology and Departments of Rheumatology, Kanazawa University Hospital, from May 2018 to July 2019 was collected with informed consent, and drug concentrations were measured by CLAM-LC-MS/MS and by chemiluminescence immunoassay (CLIA) for tacrolimus and affinity column-mediated immunoassay (ACMIA) for cyclosporin A. Correlations between the CLAM-LC-MS/MS and immunoassay results were analyzed. RESULTS: Two hundred and twenty-four blood samples from 80 patients were used for tacrolimus measurement, and 76 samples from 21 patients were used for cyclosporin A. Intra- and inter-assay precision values of quality controls were less than 7%. There were significant correlations between CLAM-LC-MS/MS and the immunoassays for tacrolimus and cyclosporin A (Spearman rank correlation coefficients: 0.861, 0.941, P < 0.00001 in each case). The drug concentrations measured by CLAM-LC-MS/MS were about 20% lower than those obtained using the immunoassays. CLAM-LC-MS/MS maintenance requirements did not interfere with clinical operations. Compared to manual pretreatment, automated pretreatment by CLAM showed lower inter-assay precision values and greatly reduced the pretreatment time. CONCLUSIONS: The results obtained by CLAM-LC-MS/MS were highly correlated with those of commercial immunoassay methods. CLAM-LC-MS/MS offers advantages in clinical TDM practice, including simple, automatic pretreatment, low maintenance requirement, and avoidance of interference.