Inflammation can downregulate CYP isoforms and alter the pharmacokinetics of certain drugs. The expression of CYP isoforms is induced by the activation of nuclear receptors, including the pregnane X receptor (PXR). This study aimed to clarify the changes in the inducibility of CYP and in vivo relevance to pharmacokinetics in an inflammatory state. We investigated the changes in the mRNA expression of Cyp3a11 induced by pregnenolone-16α-carbonitrile (PCN), a rodent PXR agonist, in the liver and small intestine of inflammation model mice generated by injection of lipopolysaccharide (LPS). The systemic effects of inflammation on CYP induction were also investigated by measuring changes in the plasma concentration of midazolam, a CYP3A substrate. Cyp3a11 mRNA expression levels in the liver and small intestine of mice were decreased by LPS treatment and increased by PCN administration. Hepatic Cyp3a11 mRNA expression levels were significantly lower in LPS- and PCN-administered mice than in PCN-administered mice, whereas intestinal Cyp3a11 mRNA expression levels were significantly higher in LPS- and PCN-administered mice than in PCN-administered mice. The plasma concentration-time profiles and area under the concentration-time curve of midazolam and its metabolite 1’-hydroxymidazolam in LPS- and PCN-administered mice tended to be higher than those in PCN-administered mice. LPS-induced inflammation may suppress the increased metabolism of midazolam by PCN, which is consistent with the hepatic Cyp3a11 mRNA expression results. Therefore, CYP inducibility via PXR activation may be attenuated in an inflammatory state. Pharmacokinetic drug-drug interactions caused by CYP induction may be altered in patients with inflammation.

Aim: In 2010, the maximum dosage of metformin was increased in Japan to the maximum dosage approved in the United States. This study aimed to evaluate the impact of the revised dosage in the package insert on metformin-associated lactic acidosis (MALA) reports in Japanese patients using the Japanese Adverse Drug Event Report (JADER) database. Methods: Adjusted reporting odds ratios of MALA was evaluated using multiple logistic regression models. Trends were analyzed using the Mann–Kendall test and Pettitt's test. Receiver operating characteristic (ROC) curve analysis was used to estimate the metformin dose that influenced MALA development. Results: The JADER database contains 845,956 reports submitted between April 2004 and March 2023. The number of adverse event reports and mean dose increased after the 2010 revision of the package insert. According to the ROC curve for lactic acidosis, the cutoff value was 1000.0 mg/day. Conclusions: Increase in metformin doses owing to regulatory actions and the recommendation of the Japan Diabetes Society may have influenced the increased MALA reporting rate, suggesting a dose-dependent relationship between the drug and MALA. The cutoff for the daily dose of metformin associated with MALA was the current maintenance dose listed in the package insert. We believe that MALA development must be carefully monitored in Japan even at the dosage specified in the package insert.

The seeds of jojoba (Simmondsia chinensis (Link) Schneider) contain approximately 50% of a unique oil known as jojoba oil. It is primarily composed of liquid wax monoesters, whose structure is similar to that of the wax component of human sebum and is widely employed as a cosmetic ingredient. Two types of jojoba oil are used in cosmetics: unrefined jojoba oil called “golden” jojoba oil and refined jojoba oil. Human sebum protects the epidermis by forming an emulsion with water, preventing water loss. In this study, the water-loss prevention and water-holding capacities of golden jojoba oil were measured and compared with those of refined jojoba oil and other oils. Golden jojoba oil exhibited the highest water-loss prevention and water-holding properties among the oils examined. These results suggest that golden jojoba oil is a useful cosmetic ingredient. Conversely, refined jojoba oil exhibited high water-loss prevention, albeit with the lowest water-holding capacity. These findings suggest that the minor components lost during the refining process are responsible for the high water-holding capacity of golden jojoba oil. When the methanol extract of golden jojoba oil was added to refined jojoba oil to examine water-loss prevention and water-holding capacity, no significant difference emerged between the two. Although the water-holding capacity of the refined jojoba oil increased, it remained lower than that of golden jojoba oil. These results suggest that, in addition to the minor substances in the methanol extract, other substances may contribute to the exceptional water-holding capacity of golden jojoba oil.