DISCONTINUOUS ORAL ABSORPTION PHARMACOKINETIC MODEL AND BIOAVAILABILITY OF 1-(2-FLUORO-5-METHYL-β-L-ARABINOFURANOSYL)URACIL (L-FMAU) IN RATS

1-(2-fluoro-5-methyl-β-L-arabinofuranosyl)uracil (L-FMAU), the L isomer of FMAU, has shown potent activity against hepatitis B virus and Epstein--Barr virus. L-FMAU showed double peaks in the plasma concentration versus time profiles following oral administration to rats, indicating discontinuous oral absorption. The objective of this study was to characterize the bioavailability and pattern of L-FMAU absorption using a pharmacokinetic model which incorporated two separate absorption processes following oral administration of the nucleoside in an animal model, the rat. Simultaneous fitting of differential equations to L-FMAU plasma concentrations following oral and intravenous administration was performed using PCNONLIN. Total clearance of L-FMAU was moderate, averaging 0·47±0·16 L h⁻¹ (mean±SD). Distributional clearance averaged 0·18±0·14 L h⁻¹. The volume of the central compartment averaged 0·30±0·09 L, and the volume of the peripheral compartment averaged 0·15±0·08 L. The first-order absorption rate constants describing the first and second absorption phases averaged 1·22±1·56 and 4·14±5·42 h⁻¹, respectively. Oral bioavailability was calculated by three methods: AUC, urinary excretion data, and a discontinuous oral absorption pharmacokinetic model. Bioavailability averaged 0·59±0·16, 0·64±0·23, and 0·63±0·13, respectively, for the three methods. The discontinuous oral absorption pharmacokinetic model is a promising new method for estimating absorption from two phases and for calculating oral bioavailability.     

COMPARATIVE BIOAVAILABILITY OF LETROZOLE UNDER FED AND FASTING CONDITIONS IN 12 HEALTHY SUBJECTS AFTER A 2·5 MG SINGLE ORAL ADMINISTRATION

Letrozole is a new non-steroidal inhibitor of the aromatase enzyme system. It is currently under development for the treatment of postmenopausal women with advanced breast cancer. To investigate the influence of food on the bioavailability of letrozole, 12 healthy male volunteers were treated under fed and fasted conditions with single oral doses of 2·5 mg letrozole in film-coated tablets. Plasma concentration profiles were determined. No significant difference in the extent of absorption (AUC or AUC_{0–8 h}) was observed between the two treatments but the rate of letrozole absorption decreased slightly under fed conditions. However, in view of the half-life of about 2 d this small change in the absorption rate is not considered to be of clinical relevance for treatment with repeated administrations. © 1997 John Wiley & Sons, Ltd.     

THE PHARMACOKINETICS OF 1954U89, 1, 3-DIAMINO-7-(1-ETHYLPROPYL)-8-METHYL-7H-PYRROLO-(3, 2-f )QUINAZOLINE,IN DOGS AND RATS AFTER INTRAVENOUS AND ORAL ADMINISTRATION

1954U89, 1, 3-diamino-7-(1-ethylpropyl)-8-methyl-7H-pyrrolo-(3, 2-f )quinazoline, is a potent, lipid-soluble inhibitor of dihydrofolate reductase. The pharmacokinetics and bioavailability of 1954U89 were examined in male beagle dogs and male CD rats. Dogs received single intravenous (2·5 mg kg⁻¹) and oral (5·0 mg kg⁻¹) doses of 1954U89 with and without successive administration of calcium leucovorin. Single intravenous (5·0 mg kg⁻¹) and oral (10 mg kg⁻¹) doses of [1,3-¹⁴C₂]1954U89 were administered to rats. Plasma concentrations of total radiocarbon were determined by scintillation counting, and intact 1954U89 was measured by HPLC. The mean plasma half-life was 3·2 ± 0·62 and 4·2 ± 0·68 h after intravenous and oral administration, respectively, to dogs. The pooled plasma half-life after intravenous administration to rats averaged 1·2 h; a reliable plasma half-life value after oral administration could not be determined. Mean total-body clearance was 2·4 ± 0·39 and 4·5 ± 1·1 L h⁻¹ kg⁻¹ after intravenous and oral administration, respectively, to dogs, and averaged 12 and 77 L h⁻¹ kg⁻¹ after intravenous and oral administration, respectively, to rats. Neither clearance nor bioavailability of 1954U89 in dogs was affected significantly by administration of calcium leucovorin. Absolute bioavailability was 54 ± 12% in dogs and 16% in rats. © 1997 John Wiley & Sons, Ltd.     

5-HT_(2A)受体基因1438A/G多态性与海洛因依赖的关系

目的··:探讨5 -HT2A 受体基因多态性与海洛因依赖易感性的关系。方法··:用聚合酶链式反应 (PCR)技术结合限制性片段长度多态性 (RFLP)分析技术 ,检测了99名海洛因依赖者和80名正常对照者5 -HT2A 受体基因1438A/G多态性的基因型和等位基因频率。结果··:海洛因依赖者5 -HT2A 受体基因1438A/G多态性基因型A1/A2的频率较对照组高。结论··:5 -HT2A 受体基因1438A/G多态性可能与海洛因依赖的易感性有关     

吸烟者与不吸烟者灰质体积的差异-基于体素的形态学研究(VBM)

目的:了解慢性吸烟者是否存在脑灰质改变。方法:采用磁共振三维成像技术对44名吸烟者和44名相匹配的不吸烟者脑结构扫描,利用基于体素的形态学分析方法进行吸烟与非吸烟者两组之间的脑灰质体积比较。结果:与不吸烟者组相比,吸烟者组的左侧丘脑、额中回区和扣带回灰质体积下降(P<0.001,未纠正)。结论:本研究发现了慢性吸烟者的脑灰质改变(丘脑、额中回区和扣带回灰质体积下降),此结果将有助于进一步研究慢性吸烟的大脑作用机制。