Hirokazu Nakanishi

Multicenter study for environmental and biological monitoring of occupational exposure to cyclophosphamide in Japan.

Purpose. A multicenter field survey of environmental contamination and exposure of healthcare professionals to anticancer drugs were performed. Setting. Three university hospitals, one cancer specialty hospital and two corporate hospitals from across Japan. Method. The environmental contamination with cyclophosphamide (CP) was investigated. A wipe examination was performed at six sites apiece in two divisions. The urinary excretion of the CP over 24 h was determined. The subjects of the survey included physicians, pharmacists, and nurses, for a total of seven at each facility irrespective of job title. The wipe samples were collected at 12 sites within two divisions at each facility. For the exposure survey, the total urine volume was determined, and a portion of the urine sample was then collected from each participants at each facility. Urine was collected for 24 h. The samples were determined by using the GC-MS method. Results. Wipe examination: contamination with CP was identified at 50% of the sites. The concentration was high (CP > 1.00 ng/cm2) in the general environment in two hospitals and in the safety cabinet in one hospital. In the survey for the exposure of staff to anticancer drugs, 276 samples were obtained from 41 healthcare professionals. CP was detected in 90 samples obtained from 23 subjects. The amount of exposure was greatly different among the facilities. The urinary excretion of CP per subject was between 2.7 and 462.8 ng/24 h. The range of urinary excretion for each hospital was between 4.6 and 211.2 ng/24 h.

Transport Mechanism of Intestinal Absorption of ü Opioid Recept or Agonists and Contribution of P-Glycoprotein in Rats and Human Intestinal Epithelial Caco-2

Abstract 1.1. Introduction: The μ opioid receptor agonists, morphine and loperamide, are widely used orally and are suggested to be P-glycoprotein (P-gp) substrates. P-gp is expressed in the brain, intestine, and various tissues in human and rats. In the intestine, P-gp limits the absorption of certain drugs such as opioids; however, the underlying mechanism has not been elucidated. The aim of the present study was to examine the intestinal transport characteristics of morphine and loperamide and the role of P-gp in their transport process. 1.2. Method: Transcellular transport studies were conducted using isolated rat intestinal tissue mounted in an Ussing-type chamber. Bidirectional permeability and inhibition transport studies were performed using Caco-2 cell lines. The intestinal absorption was examined by an in situ closed-loop method in rats. 1.3. Results: Loperamide showed secretory transport across rat intestinal tissue and Caco-2 cells, and P-gp substrates cyclosporine A and rhodamine 123 inhibited this transport. In the intestinal loop experiment in rats, the accumulation of loperamide in the intestinal tissue increased upon adding cyclosporine A and rhodamine 123. In contrast, morphine showed no directional transport and P-gp inhibitory effects across rat intestinal tissue. In Caco-2 cells, morphine transport was found to be secretory-directed and this transport was inhibited by cyclosporine A and rhodamine 123, but to a much lesser extent than that of loperamide. Morphine disappearance and accumulation were unaffected upon the addition of cyclosporine A and rhodamine 123. 1.4. Conclusion: These results suggest that P-gp contributes significantly to the secretory transport of loperamide but negligibly to that of morphine in the small intestine. In conclusion, intestinal transport of both morphine and loperamide is found to be secretory-directed. P-gp partially contributes to this secretory-directed transport. Thus, P-gp is prominent in loperamide rather than morphine transport.

Absorption process of salazosulfapyridine in human intestinal epithelial cells and rat intestine

Introduction: Salazosulfapyridine (SASP) is an oral medication used to treat rheumatoid arthritis and inflammatory bowel disease, particularly ulcerative colitis. It has been reported that various transporters such as P-glycoprotein (Pgp) and multidrug resistance-associated protein 2 (MRP2), are involved in the transport of SASP. P-gp and MRP2 are expressed in the brain, intestine, and various tissues in both humans and rats. In the intestine, P-gp limits the absorption of certain drugs, however, its mode of absorptive action with regard to SASP has not, as of yet been studied. The aim of this study was to investigate the intestinal transport of SASP and examine whether transporters such as P-gp and MRP2 are involved in this process. Method: Bidirectional permeability and inhibition transport studies were performed using Caco-2 and T84 cell lines. Transcellular transport studies were conducted using isolated rat intestinal tissue mounted in an Ussing-type chamber. The intestinal absorption was examined using an in-situ closed-loop experiment in rats. Results: SASP showed secretory-directed transport across Caco-2 and T84 cells, as well as rat intestinal tissue. Cyclosporine A (CsA), a P-gp inhibitor, was found to decrease this secretory-directed transport. In the intestinal closedloop experiment, addition of CsA resulted in increased accumulation of SASP; however, this was too miniscule to be considered. The inhibition study showed that both secretory and absorptive transporters sensitive to probenecid are involved in the process of SASP absorption in the small intestine. Conclusion: In the process of SASP absorption in the intestine, CsA-sensitive secretory transporters including P-gp as well as probenecid-sensitive absorptive and secretory-transporters are involved and the total of the absorption of SASP is regulated by these transporters. It is likely that these transporters are coordinated in a complex manner to effectively regulate absorption of SASP and other biochemically similar drugs.