A rapid screening system has been established to extract novel candidates that exhibit potent inhibition of the transport of fluorescent substrate by organic anion transporting polypeptide (OATP) 1B3. OATP1B3 is abundantly expressed in solid digestive organ cancers. Thus, the identification of new substrates leads to novel strategies for effective cancer chemotherapy with minimal adverse effects. We used an automated image substrates for OATP1B3, we performed transport assays in OATP1B3-expressing cells. We determined that SN-38 is a novel substrate for OATP1B3. In conclusion, our results demonstrate that the screening system established in this study is a useful method for the rapid extraction of candidate therapeutic agents from the large numbers of compounds.
The objective of this study was to determine the effect of a marathon run on serum lipid and lipoprotein concentrations and serum muscle enzyme activities and follow their recovery after the run. These blood concentrations were measured before, immediately after, and serially after a marathon run in 15 male recreational runners. The triglyceride level was significantly elevated postrace, then fell 30% below baseline 1 day after the run, and returned to baseline after 1 week. Total cholesterol responded less dramatically but with a similar pattern. High-density lipoprotein cholesterol remained significantly elevated and low-density lipoprotein cholesterol was transiently reduced for 3 days after the run. The total cholesterol/high-density cholesterol ratio was significantly lowered for 3 days. Serum lactate dehydrogenase activity significantly doubled postrace and then declined but remained elevated for 2 weeks. Serum creatine kinase activity peaked 24 hr after the run, with a 15-fold rise, and returned to baseline after 1 week. The rise of these enzymes reflects mechanically damaged muscle cells leaking contents into the interstitial fluid. It is concluded that a prolonged strenuous exercise bout in recreational runners, such as a marathon, produces beneficial changes in lipid blood profiles that are significant for only 3 days. However, muscle damage is also evident for 1 week or more from the dramatic and long-lasting effect on enzyme levels. Laboratory values for these runners were outside normal ranges for some days after the race.
The effects of habitual cigarette smoking on cardiorespiratory responses to sub-maximal and maximal work were evaluated in nine adult nonsmokers and nine smokers with a mean age of 33 yr. A maximal treadmill test was followed by three tests at 45, 60 and 75% of each subject's VO 2 max. Compared to nonsmokers, the habitual smokers had a non-significantly lower VO 2 max in L/min and per lean body mass (9 and 6%, respectively), but had higher %fat (pϽ0.01), resulting in a significantly lower VO 2 max per kg body wt (13%, pϽ0.03). Maximal exercise ventilation (V E ) was 16% lower in smokers. During sub-maximal work at equivalent exercise stress levels in the two groups, the V E /VO 2 ratio was higher in smokers by an average of 11% because VO 2 was lower and the respiratory exchange ratio values were significantly elevated in smokers at 75% of VO 2 max. Blood lactate concentrations in smokers were higher as workloads increased and O 2 pulse (VO 2 /HR) was significantly lower throughout, indicating reduced O 2 extraction, probably due to carbon monoxide. The resting HR was significantly higher in smokers and the HR recovery following all three submaximal exercises was significantly slower in smokers. These results show that detrimental cardiorespiratory effects of chronic cigarette smoking in apparently healthy individuals are evident at moderate exercise levels as reduced gas exchange efficiency in lungs and muscles.
Hepatic organic anion transporters OATP1B1 and OATP1B3 are expressed at the sinusoidal membrane of hepatocytes and contribute to the hepatic uptake of a wide variety of clinically used drugs. To identify the antibiotics that interact with the human organic anion transporters OATP1B1 and OATP1B3, we applied a screening system using fluorescent probes. Twenty-six antibiotics with a variety of mechanisms of action were examined. The screening demonstrated that four antibiotics inhibited OATP1B1-mediated transport and 11 antibiotics inhibited OATP1B3-mediated transport in a concentration-dependent manner. Antibiotics that inhibited OATP1B3-mediated transport tended to exhibit higher affinity than those that inhibited OATP1B1-mediated transport. To clarify whether the antibiotics that interacted with OATP1B1 and/or OATP1B3 were substrates for these transporters, an uptake study was performed. Rifampicin and penicillin were transported by both OATP1B1 and OATP1B3. Moreover, OATP1B3 was involved in the transport of ceftriaxone, cefmetazole, cefoperazone, and cefotaxime. Macrolides were not significantly transported by either transporter. In conclusion, the results demonstrated that our system is a useful method for the rapid screening of transporter-antibiotic interaction, and we found novel substrates. Our results indicate that OATP1B1 and/or OATP1B3 contribute to the transport process of some antibiotics, and that drug-drug interactions associated with these transporters could occur after the administration of antibiotics.
The purpose of this study was to determine the influence of a 6-month unsupervised, flexible and fairly light intensity walking program on endurance fitness, strength, lipids and lipoproteins and bone health in a group of middle-aged sedentary women. Six pre-menopausal and 8 post-menopausal women, aged 54 yr, served as the walk training group (W) and 9 women (2 post-menopausal), aged 49yr, served as controls (C). W walked an average of 10,000 steps per day for 6 months, which included an average of 5,000 steps of brisk walking for 30 min, 4 to 5 days per week. Workloads, heart rates and double-product break point (during incremental maximal ergometer exercise), body weight and %fat, serum lipids, leg strength and bone density (by ultrasound) and induces of bone metabolism were measured at baseline and after 3 and 6 months. Walk training in W resulted in a significant improvement in maximal workload during the exercise test compared with C. Double product break point in W during exercise significantly shifted towards higher workloads and resting heart rate was reduced. Isokinetic muscular strength of leg extensors and abdominal muscular endur ance measured by situps were also significantly increased in W. Estimated calcaneal bone density showed a tendency to increase after 6 months of training in W. Indicators of bone resorption and growth remained unchanged. Changes in serum lipids and lipoproteins were also favorable, but not significant. In conclusion, these results show that a flexible and self-regulated walking program is sufficient to elicit improvements in cardiovascular endurance, aerobic capacity measured by DPBP and strength of leg and abdominal muscles. Bone strength and serum lipids were not clearly improved after 6 months with this walking program. If training time were extended to 12 months, significant improvements in these measures can be expected because tendencies toward improve ments were observed.
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