Direct inhibition and down-regulation by uremic plasma components of hepatic uptake transporter for sn-38, an active metabolite of irinotecan, in humans

Purpose: Clinical study has previously revealed that plasma concentration of 7-ethyl-10-hydroxycamptothecin (SN-38), an active metabolite of irinotecan, was higher in patients with end-stage renal failure than those with normal kidney function although SN-38 is mainly eliminated in the liver. Here, we focused on inhibition by uremic toxins of hepatic SN-38 uptake and down-regulation of uptake transporter(s) by uremic plasma in humans. Methods: We evaluated SN-38 uptake and its inhibition by uremic toxins, 3-carboxy-4-methyl-5-propyl-2-furanpropionate (CMPF), indoxyl sulfate (Indox), hippuric acid (HA) and indole acetate (IA), with cryopreserved human hepatocytes and HEK293 cells stably expressing hepatic uptake transporters, organic anion transporting polypeptides (OATPs). We also collected plasma samples from patients with severe renal failure to examine their effects on mRNA level of OATPs in primary cultured human hepatocytes. Results: SN-38 was taken up by hepatocytes, which showed biphasic saturation patterns. The SN-38 uptake by hepatocytes was significantly inhibited by a uremic toxin mixture including clinically relevant concentrations of CMPF, Indox, HA and IA. Kinetic analyses for OATP-mediated transport revealed that the uptake of SN-38 by OATP1B1 was the highest, followed by OATP1B3. Among the uremic toxins, CMPF exhibited most potent inhibition of OATP1B1-mediated SN-38 uptake and directly inhibited the uptake of SN-38 also in hepatocytes. In addition, gene expression of OATP1B1 and OATP1B3 in hepatocytes was significantly down-regulated by the treatment with the uremic plasma. Conclusions: OATP1B1-mediated hepatic uptake of SN-38 was inhibited by uremic toxins, and gene expression of OATP1B1 was down-regulated by uremic plasma. © 2013 Springer Science+Business Media New York

The Difficulty of Diagnosing Invasive Aspergillosis Initially Manifesting as Optic Neuropathy

Background: Invasive aspergillosis is often fatal. Here, we report a patient with invasive aspergillosis primarily involving the optic nerve diagnosed on autopsy. Case Presentation: A 77-year-old female with underlying diabetes mellitus, hyperlipidemia, and hypertension presented with disc swelling of the left eye. Although mini-pulse steroid therapy improved visual acuity (VA) of the left eye, it abruptly decreased to no light perception within a month, followed by a decrease in VA of the right eye to 0.5. At referral, VA was 0.3 in the right eye, and there was no light perception in the left eye. Results: Fundus examination revealed optic disc swelling of both eyes. Goldmann perimetry showed irregular visual field defects, whereas magnetic resonance imaging (MRI), general, and cerebrospinal fluid (CSF) examinations revealed no distinct abnormalities. We suspected anterior ischemic optic neuropathy and invasive optic neuropathy. As with the left eye, steroid pulse therapy temporarily improved VA of the right eye and then decreased to 0.2. Additional anticoagulant therapy did not improve VA. Concurrent to therapy, the patient became febrile with depressed consciousness. Repeat MRI identified suspected midbrain infarction, and CSF examination indicated cerebral meningitis. In spite of administering transfusions and antibiotics, she died on hospital day 40. Autopsy revealed large amounts of Aspergillus hyphae mainly localized in the dura mater of the optic nerve and destruction of the cerebral artery wall, suggesting an etiology of subarachnoid hemorrhage. Conclusions: When examining refractory and persistent disc swelling, we should rule out fungal infections of the optic nerve