The pharmacokinetics of Luteolin ( Lut ) solution in rabbits and rats was investigated. Lut in plasma, bile and urine as well as protocatechuic acid (which is a product of Lut) in plasma and urine were determined by fluorescence spectrophotometry. A curve with multiple peaks was fitted to the data of plasma concentration versus time, employing a nonlinear program developed with an IBM-PC computer. The results indicated that the data set obtained with 30 mg /kg doses by iv fitted well to a peculiar open 3 compartment model involved in the enterohepatic recirculation of the drug and the undulations of the drug concentration.The essential pharmacokinetics parameters (mean?SD) were as follows; The t1/2 values for the ?-phase and ?-phase were about 0.18?0.01 h and 1.66?0.24 h respectively. The apparent volume of distribution ( Vd) was about 1.43? 0.45 L?kg-1. The reabsorption rate constant ( Ka ) was 0.465? 0.08 h-1 The reabsorption percent ( F' ) was about 6.9? 2.1% . The elimination rate constant was 1.124?0.35 h-1. The clearance was 588?113 ?g?h-1?kg-1. This study indicated that Lut was rapidly removed from the blood by both kidney and liver where Lut was excreted by way of the bile into intestine from which it Was reabsorbed. The 12 h urine excretion of Lut in rabbits was in the order of 37.7% of total iv dose. In rats, the 6 h bile excretion of Lut was about 11.2% of that total iv dose. A comparison of the C-T curve of PCA with of Lut suggested that PCA was the one of the products of Lut.In rats, the 3H-Lut orally administered was widely distributed in the tissues, the concentrations being higher in liver and kidney.

OBJECTIVE: To trace a rare case of chronic myeloid leukemia (CML) with a four-way Philadelphia chromosome variant by cytogenetic analysis in order to provide a basis for the selection of treatment. METHODS: Bone marrow morphology, chromosomal karyotyping, fluorescence in situ hybridization (FISH) and real-time quantitative PCR (RQ-PCR) were used for the diagnosis and staging of the disease. Point mutations in the tyrosine kinase domain of ABL1 gene were detected by Sanger sequencing. RESULTS: The patient was initially diagnosed as CML in chronic phase (CML-CP) with a chromosomal karyotype of 46,XX,t(5;9;22;6)(q13;q34;q11;q25), while FISH revealed presence of a variant Philadelphia chromosome translocation. Clonal evolution has occurred after 38 months of tyrosine kinase inhibitor (TKI) treatment, when cytogenetic analysis revealed coexisting t(5;9;22;6)(q13;q34;q11;q25) and t(5;9;22;6;17)(q13;q34;q11;q25;q11). After 57 months of TKIs treatment, only the t(5;9;22;6;17) clone was detected. Three months later, hyperdiploidy with additional abnormalities were detected in addition to t(5;9;22;6;17). Three mutations, including p.Tyr253Phe, p.Thr315Ile and p.Gly250Glu, were identified in the tyrosine kinase domain of the ABL1 gene during the course of disease. The patient did not attain cytogenetic and molecular response to TKIs. CONCLUSION The four-way variant translocation may be genetically unstable. Clonal evolution and genetic mutations are likely to occur during TKIs treatment, resulting in poor response to drug therapy. This observation, however, needs to be confirmed by large-scale studies.
Enzyme Inhibitors/therapeutic use* ; Evolution, Molecular ; Female ; Humans ; In Situ Hybridization, Fluorescence ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics* ; Mutation/genetics* ; Philadelphia Chromosome ; Translocation, Genetic