Results obtained in rats or mice on the pharmacokinetics of acandidate therapeutic drug don't always apply in humans.

One reason, apparently, is because a change of as little as oneamino acid in the sequence of otherwise homologous drugreceptors can dramatically affect the receptor's drug-bindingabilities.

In particular, researcher Avi Ashkenazi of Genentech Inc. andhis collaborators have found that the human and rat receptorsfor the neurotransmitter 5-hydroxytryptamine (5-HT), whilebinding 5-HT with comparable high affinity, are very differentin their respective abilities to bind a variety of beta-adrenergicreceptor antagonists, a serotonergic agonist, and severalserotonergic drugs, including sumatriptan for migraineheadaches.

Reporting in Thursday's Nature, Ashkenazi and hiscollaborators at Stanford University School of Medicine and theUniversity of Toronto showed that the critical differencebetween the rat and human 5-HT receptors resides in oneamino acid residue, which is located in the seventh of the eighttransmembrane domains that go to form the receptor's ligandbinding pocket. The researchers found that if they replaced thethreonine at residue 355 in the human receptor withasparagine (which occupies that position in the rat receptor), it"rendered the pharmacology of the receptors essentiallyidentical."

These results especially speak to designing drugs to treatneuropsychiatric disorders such as anxiety, migraine,depression and epilepsy since they may interact with differentsubtypes of the 5-HT receptor.

And generally they are a reminder and a warning that "drug-receptor interactions should not be extrapolated from animal tohuman species without verification," the authors concluded.

"It's becoming clear in several cases that small differences instructure that people have assumed are insignificant areturning out to be significant, especially in terms ofpharmacology," Ashkenazi told BioWorld.

-- Jennifer Van Brunt Senior Editor

(c) 1997 American Health Consultants. All rights reserved.

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