Pharmacogenetics of Drugs Withdrawn From the Market

Wei Zhang; Mary W Roederer; Wang-Qing Chen; Lan Fan; Hong-Hao Zhou


Pharmacogenomics. 2012;13(2):223-231. 

In This Article


In February 2000, alosetron was approved by the FDA as a medicine for irritable bowel syndrome in women. Initial use of alosetron was widespread, with more than 300,000 patients receiving the treatment.[11] However, between February and November, the FDA had received over 70 reports of severe adverse events of this drug, including 49 cases of ischemic colitis, two cases of severe constipation, and three cases of death.[12] Although it was reported that the rate of ischemic colitis was 0.95‰ and the rate of severe constipation was 10–43%, respectively,[13] alosetron was voluntarily withdrawn from the American market, while reintroduced in 2002 with a more restricted indication and a prescribing program.[12] Serotonin (5-HT) can promote the gut motility, while alosetron would inhibit its motility, for alosetron is a 5-HT3 antagonist.[14] It was postulated that the serotonin transporter (5-HTT) encoded by SLC6A4 was responsible for the reuptake of serotonin from the synaptic space. Therefore, a highly efficient 5-HTT cleared 5-HT from the synapse more rapidly, then less 5-HT remains in the synapse and less alosetron was needed to block the 5-HT3 receptor.[14] Constipation-related irritable bowel syndrome had a very limited response to meal ingestion, with a low concentration of 5-HT.[15] It was conceivable that a reduced endogenous 5-HT function on motor and secretor functions may ultimately lead to constipation.[16] The polymorphisms in the promoter region of SLC6A4 can affect the absorption and transport of alosetron in the body. The serotonin transporter gene-linked polymorphic-region polymorphism resulted in short (S) and long (L) alleles, based on the presence or absence of a 44-bp insertion.[14] The variations of the serotonin transporter gene-linked polymorphic-region would influence colonic transit in diarrhea-related irritable bowel syndrome patients treated with alosetron. The LS/SS genetic variation would be expected to reduce reuptake of serotonin. The L allele shows a greater slowing of colonic transit (p = 0.039), and was more frequent in L homozygous than heterozygous patients (p = 0.024).[14] So, it is possible that when treated with alosetron, the L allele may increase the risk of constipation through the reduced 5-HT concentration. However, the clinical significance needs further confirmation.


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