Intestinal cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp) both play a vital role in the metabolism of oral cyclosporine (CsA). We investigated the genetic polymorphisms in CYP3A4(promoter region and exons 5, 7 and 9) and MDR1 (exons 12, 21 and 26) genes and the impact of these polymorphisms on the pharmacokinetics of oral CsA in stable heart transplant patients (n = 14). CYP3A4 polymorphisms were rare in the Asian population and transplant patients. Haplotype analysis revealed 12 haplotypes in the Chinese, eight in the Malays and 10 in the Indians. T-T-T was the most common haplotype in all ethnic groups. The frequency of the homozygous mutant genotype at all three loci (TT-TT-TT) was highest in the Indians (31%) compared to 19% and 15% in the Chinese and Malays, respectively. In heart transplant patients, CsA exposure (AUC(0-4 h), AUC(0-12 h) and C(max)) was high in patients with the T-T-T haplotypes compared to those with C-G-C haplotypes. These findings suggest that haplotypes rather than genotypes influence CsA disposition in transplant patients.

• Although conventional CT is useful for diagnosis of SRMs, it has limitations. • Machine-learning based CT texture analysis facilitate differentiation of small AMLwvf from RCC. • The highest accuracy of SVM-RFE+SMOTE classifier reached 93.9 %. • Texture analysis combined with machine-learning methods might spare unnecessary surgery for AMLwvf.

No abstract

Purpose: As combination chemotherapy of antiangiogenic agents with conventional chemotherapeutic drugs continues to evolve, an understanding of the pharmacokinetic and pharmacodynamic variables associated with optimal treatment is needed. Thus, the effect of the multitargeted tyrosine kinase inhibitor sunitinib on tumor distribution of temozolomide was investigated to evaluate conditions for optimal combination chemotherapy. Experimental Design: In mice bearing SF188V+ human glioma xenografts, measurements of temozolomide pharmacokinetic properties and sunitinib pharmacodynamic activities were evaluated, the latter including determinants for vascular normalization, including CD31, collagen IV, and a-SMA. Results: Sunitinib given in a daily dose of either 10 or 40 mg/kg orally over 14 days increased temozolomide tumor distribution, as indicated by the tumor-to-plasma AUC ratio compared with control; however, only the 10 mg/kg group reached statistical significance (P < 0.05). From the pharmacodynamic analysis, a''vascular normalization index'' incorporating the microvessel density (MVD) and protein expression of a-SMA and collagen IV was proposed as an indication of the number of tumor vessels with relatively good quality, which was found to be significantly correlated with the unbound temozolomideAUC in tumor interstitial fluid (P = 0.05). Furthermore, both sunitinib-treated groups maintained the molecular balance between angiopoietins Ang-1 and Ang-2, suggesting a critical role of angiopoietins in vascular normalization. Conclusions: Several important factors relevant to the antiangiogenic agent^induced tumor vascular normalization have been identified and incorporated into a vascular normalization index that may serve to correlate the angiogenic phenotype to the distribution of cytotoxic drugs in solid tumors.