The full content of Annals is available to subscribers

Subscribe/Learn More  >
Original Research |

In-Vitro Assessment of a Hypersensitivity Syndrome Associated with Sorbinil

Stephen P. Spielberg, MD, PhD; Neil H. Shear, MD; Marilyn Cannon; Nancy J. Hutson, PhD; and Kare Gunderson, MD
[+] Article, Author, and Disclosure Information

Grant Support: In part by grants from the Sunnybrook Trust for Medical Research, Medical Research Council of Canada (MT-7489 and MA 9716) and the Central Research Division of Pfizer, Inc. Dr. Spielberg is a Medical Research Council Scholar. Dr. Shear is a Career Scientist of the Ontario Ministry of Health.

Requests for Reprints: Neil H. Shear, MD, Head, Division of Clinical Pharmacology, Sunnybrook Health Science Centre A3, 2075 Bayview Avenue, Toronto, Ontario, Canada M4N 3M5.

Current Author Addresses: Dr. Spielberg: Director, Clinical Pharmacology and Toxicology, Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada M5G 1X8.

Dr. Shear: Head, Division of Clinical Pharmacology, Sunnybrook Health Science Centre A3, 2075 Bayview Avenue, Toronto, Ontario, Canada M4N 3M5.

Dr. Hutson: Department of Metabolic Diseases, Central Research Division, Pfizer, Inc., Groton, CT 06340.

Ann Intern Med. 1991;114(9):720-724. doi:10.7326/0003-4819-114-9-720
Text Size: A A A

Sorbinil is a hydantoin aldose reductase inhibitor that has shown promise as therapy for patients with diabetic complications such as neuropathy and retinopathy. However, as many as 10% of patients receiving sorbinil have had adverse reactions characterized by fever, skin rash, and myalgia. Our previous studies of phenytoin suggested that susceptibility to reactions might result from an inherited detoxification defect. We did the current study to determine if sorbinil is metabolized to reactive intermediates and if cells from patients with a history of a reaction to sorbinil are appropriate for the in-vitro investigation of susceptibility. Microsome-generated metabolites of sorbinil (50 µM) were toxic to normal peripheral blood lymphocytes (7.9% ± 0.3% dead cells [mean ± SE]). Toxicity was increased in the presence of an epoxide hydrolase inhibitor (17.5% ± 0.3% dead cells) and abolished by an inhibitor of cytochrome P-450. In contrast to cells from healthy controls and diabetics who tolerated sorbinil (7.9% ± 0.7% and 7.8% ± 0.4% dead cells, respectively), cells from the six patients who had sorbinil reactions showed significantly increased toxicity from metabolites of sorbinil and phenytoin (19.7% ± 2.3% dead cells, P < 0.001). Cells from three patients who had reactions to phenytoin were similarly sensitive to sorbinil metabolites (23.4% ± 0.3% dead cells). We conclude that sorbinil is oxidatively metabolized to a potentially toxic intermediate. Certain patients may be at increased risk for developing hypersensitivity reactions. Development of this important new drug has been hampered by uncommon but potentially severe reactions. An increased understanding of the steps involved in the development of adverse reactions could lead to screening tests or to the development of safer compounds.





Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).


Submit a Comment/Letter
Submit a Comment/Letter

Summary for Patients

Clinical Slide Sets

Terms of Use

The In the Clinic® slide sets are owned and copyrighted by the American College of Physicians (ACP). All text, graphics, trademarks, and other intellectual property incorporated into the slide sets remain the sole and exclusive property of the ACP. The slide sets may be used only by the person who downloads or purchases them and only for the purpose of presenting them during not-for-profit educational activities. Users may incorporate the entire slide set or selected individual slides into their own teaching presentations but may not alter the content of the slides in any way or remove the ACP copyright notice. Users may make print copies for use as hand-outs for the audience the user is personally addressing but may not otherwise reproduce or distribute the slides by any means or media, including but not limited to sending them as e-mail attachments, posting them on Internet or Intranet sites, publishing them in meeting proceedings, or making them available for sale or distribution in any unauthorized form, without the express written permission of the ACP. Unauthorized use of the In the Clinic slide sets will constitute copyright infringement.


Buy Now for $42.00

to gain full access to the content and tools.

Want to Subscribe?

Learn more about subscription options

Related Articles
Related Point of Care
Topic Collections
PubMed Articles
Forgot your password?
Enter your username and email address. We'll send you a reminder to the email address on record.