Desta Zeruesenay, Soukhova Nadia, Flockhart David A
Division of Clinical Pharmacology, Department of Medicine, Georgetown University Medical Center, Washington, DC, USA.
J Clin Psychopharmacol. 2002 Apr;22(2):162-8. doi: 10.1097/00004714-200204000-00009.
Pimozide is often coprescribed with serotonin reuptake inhibitor (SSRI) antidepressants to treat depression in patients with Tourette's syndrome. In human liver microsomes (HLMs), the inhibition of the primary route of pimozide metabolism, N-dealkylation to 1,3-dihydro-1-(4-piperidinyl)-2H-benzimidazol-2-one (DHPBI), by four SSRIs (fluoxetine, sertraline, paroxetine, and fluvoxamine) and azithromycin was tested. Inhibition constants (K(i) values) were estimated from Dixon plots (three HLMs for each inhibitor) using the appropriate enzyme inhibition model by nonlinear regression. At 10 microM paroxetine, sertraline, fluoxetine, or fluvoxamine, the formation of DHPBI from pimozide (10 microM) in HLMs was inhibited by an average (three HLMs) of 7%, 7.7%, 8%, and 16%, respectively, whereas this inhibition did not exceed 55% at the maximum concentrations (100 microM) of the SSRIs tested. Azithromycin had negligible effect on pimozide (10 microM) N-dealkylation (19% at 100 microM azithromycin). These inhibition data were compared with ketoconazole, which was included as a positive control of CYP3A inhibition. At 0.1 microM and 0.5 microM ketoconazole, the formation of DHPBI from 10 microM pimozide was inhibited by 32% and 62%, respectively. The K(i) values (+/- SD) of ketoconazole, sertraline, fluvoxamine, azithromycin, fluoxetine, and paroxetine were 0.07 microM, 89 +/- 44 microM, 89 +/- 24 microM, 103 +/- 52 microM, 117 +/- 27 microM, and 129 +/- 33 microM, respectively. These values are least 100-fold higher than the expected plasma concentrations after the usual daily doses of the SSRIs and azithromycin, suggesting that coadministration of SSRIs and azithromycin are unlikely to markedly diminish the elimination of pimozide in patients. However, in vivo predictions from in vitro data are not always perfect. In vivo, the SSRIs or azithromycin may concentrate in the liver relative to plasma. In addition, the possibility that these drugs could alter pimozide disposition through effects on transport proteins or via promoter repression cannot be ruled out.
匹莫齐特常与5-羟色胺再摄取抑制剂（SSRI）类抗抑郁药联合使用，以治疗患有妥瑞氏综合征患者的抑郁症。在人肝微粒体（HLM）中，测试了四种SSRI（氟西汀、舍曲林、帕罗西汀和氟伏沙明）及阿奇霉素对匹莫齐特代谢主要途径（N-脱烷基生成1,3-二氢-1-(4-哌啶基)-2H-苯并咪唑-2-酮（DHPBI））的抑制作用。使用适当的酶抑制模型通过非线性回归从Dixon图（每种抑制剂用三个HLM）估算抑制常数（K(i)值）。在10微摩尔/升的帕罗西汀、舍曲林、氟西汀或氟伏沙明作用下，HLM中匹莫齐特（10微摩尔/升）生成DHPBI的过程平均（三个HLM）分别被抑制了7%、7.7%、8%和16%，而在所测试的SSRI最大浓度（100微摩尔/升）下，这种抑制作用未超过55%。阿奇霉素对匹莫齐特（10微摩尔/升）的N-脱烷基作用影响可忽略不计（100微摩尔/升阿奇霉素时为19%）。将这些抑制数据与酮康唑进行比较，酮康唑作为CYP3A抑制的阳性对照。在0.1微摩尔/升和0.5微摩尔/升的酮康唑作用下，10微摩尔/升匹莫齐特生成DHPBI的过程分别被抑制了32%和62%。酮康唑、舍曲林、氟伏沙明、阿奇霉素、氟西汀和帕罗西汀的K(i)值（±标准差）分别为0.07微摩尔/升、89±44微摩尔/升、89±24微摩尔/升、103±52微摩尔/升、117±27微摩尔/升和129±33微摩尔/升。这些值比SSRI和阿奇霉素常规日剂量后预期的血浆浓度至少高100倍，这表明SSRI和阿奇霉素联合给药不太可能显著降低患者体内匹莫齐特的消除。然而，体外数据的体内预测并不总是完美的。在体内，SSRI或阿奇霉素相对于血浆可能在肝脏中富集。此外，不能排除这些药物通过对转运蛋白的影响或通过启动子抑制来改变匹莫齐特处置的可能性。
