ABSTRACT
OBJECTIVES: Although sirolimus tablets and oral solutions have been used in clinical practice, no study has been reported on the pharmacokinetics and bioavailability of a single-dose of sirolimus tablets in healthy Chinese volunteers. The purpose of this study was to compare the bioavailability and pharmacokinetic (PK) properties of two different 1-mg sirolimus tablets in healthy Chinese male volunteers and evaluate whether a generic tablet of sirolimus meets the criteria for bioequivalence from the State Food and Drug Administration (SFDA) of China when compared with a reference product. MATERIALS AND METHODS: A total of 24 healthy Chinese volunteers was eligible for this 6 mg single dose, randomized-sequence, open-label, 2-period crossover study. Blood samples were collected before dosing and at 0.25, 0.50, 0.75, 1.0, 1.5, 2, 3, 4, 8, 12, 24, 48, 72, 120, 168, 216, and 264 hours after dosing. Whole blood sirolimus concentration was analyzed by a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. Pharmacokinetic properties of sirolimus were assessed using noncompartmental analysis. RESULTS: The mean (range) Cmax values of the test and the reference were 15.25 (8.48 - 24.40) and 13.43 (7.90 - 22.90) ng/ml; AUC0-t values were 475.65 (293.33 - 1049.86) and 451.96 (221.52 - 809.11) ng/h/ml. The medians (range) tmax values were 2.0 (1.0 - 8.0) and 2.0 (1.0 - 8.0) hours, respectively. The 90% confidence intervals (CIs) for the ratios of Cmax, AUC0-264, and AUC0-∞ were 103.7% to 124.4%, 97.5% to 113.6%, and 98.0% to 114.8%, respectively. CONCLUSION: In this single-dose crossover study the test sirolimus tablets met the criteria for bioequivalence in terms of both rate and extent. Each sirolimus formulation was well tolerated during the study.
Subject(s)
Sirolimus/pharmacokinetics , Adult , Area Under Curve , Asian People , Biological Availability , Chemistry, Pharmaceutical , Cross-Over Studies , Drugs, Generic/pharmacokinetics , Healthy Volunteers , Humans , Male , Sirolimus/administration & dosage , Sirolimus/blood , Tablets/pharmacokinetics , Therapeutic Equivalency , United States , United States Food and Drug Administration , Young AdultABSTRACT
OBJECTS: MicroRNAs have been found in the developing central nervous system, but little is known about their functions in development, especially in the abnormal development of spinal cord in spina bifida. To this end, we have studied the mechanism of microRNAs involved in the morphogenesis of the spinal cord in all-trans-retinoic acid (RA)-treated spina bifida rat fetus. MATERIALS AND METHODS: Timed-pregnant rats were gavage-fed RA, and embryos were obtained on 13.5, 15.5, 17.5, and 19.5 days. MicroRNAs' expression profile was analyzed by Northern blot. In situ apoptosis detection and microRNA in situ hybridization methods on sections of paraffin-embedded tissues were employed to explore the mechanism. CONCLUSION: Administration of RA reduced the size of the spinal cord, probably as a consequence of increased cell death. There is a dramatic decrease in the expression of miR-9/9*, miR-124a and miR-125b, and Bcl2 and P53 as well in the sacral cord from E13.5 to E19.5 days post coitum. Our data showed that expression of these microRNAs was dysregulated in RA-treated spinal cord during embryonic development, suggesting that they may be involved in the development of the spinal cord.