Basilua Joe Miantezila, Sawoo Olivier, Mangin Irène, Dossou-Yovo Flore, Boussard Aline, Chevillard Lucie, Lutete Gaston T, Eto Bruno, Peytavin Gilles, Pochart Philippe
EA4065 Intestinal Ecosystem, Probiotics, Antibiotics, Paris Descartes University SPC, Paris, France.
Clinical Pharmacology Unit, University of Kinshasa, Kinshasa, Democratic Republic of Congo.
Curr Drug Metab. 2019;20(11):898-906. doi: 10.2174/1389200220666191023105609.
Cotrimoxazole (TMP-SMX) is concomitantly used as a primary prophylaxis of opportunistic infections with antiretroviral agents, such as Atazanavir (ATV). Results from an ex vivo study showed changes in intestinal absorption of ATV when rats were pretreated with TMP-SMX. The objective of this in vivo study is to determine the effect of TMP-SMX on the pharmacokinetics of ATV in rats. We also studied changes in gut microbiota induced by TMP-SMX.
We used the non-compartment analysis to compare the pharmacokinetics of ATV in a parallel group of rats treated with a low or therapeutic dose of TMP-SMX for nine days to untreated control rats. Gut microbiota was characterized using qPCR and High Throughput Sequencing of 16S rDNA.
Rats treated with TMP-SMX showed a much broader exposure to ATV compared to the control group (AUC0-8h (ng.mL-1.h), 25975.9±4048.7 versus 2587.6±546.9, p=0.001). The main observation regarding the gut microbiota was a lower proportion of enterobacteria related to the administration of TMP-SMX. Moreover, the Total Gastrointestinal Transit Time (TGTT) was longer in the TMP-SMX treated group.
Concomitant administration of TMP-SMX and ATV significantly increased ATV exposure in rats. This increase could be the result of a prolonged TGTT leading to an increase in the intestinal residence time of ATV favoring its absorption. Gut microbiota changes induced by TMP-SMX could be at the origin of this prolonged TGTT. If demonstrated in humans, this potential interaction could be accompanied by an increase in the adverse effects of ATV.
复方新诺明（TMP-SMX）与抗逆转录病毒药物如阿扎那韦（ATV）同时用作机会性感染的一线预防用药。一项体外研究结果显示，用TMP-SMX预处理大鼠后，ATV的肠道吸收发生了变化。本体内研究的目的是确定TMP-SMX对大鼠体内ATV药代动力学的影响。我们还研究了TMP-SMX诱导的肠道微生物群变化。
我们采用非房室分析方法，比较了用低剂量或治疗剂量的TMP-SMX处理9天的大鼠与未处理的对照大鼠体内ATV的药代动力学。使用qPCR和16S rDNA高通量测序对肠道微生物群进行表征。
与对照组相比，接受TMP-SMX治疗的大鼠体内ATV的暴露量显著更高（AUC0-8h（ng·mL-1·h），25975.9±4048.7对2587.6±546.9，p = 0.001）。关于肠道微生物群的主要观察结果是，与TMP-SMX给药相关的肠杆菌比例较低。此外，TMP-SMX治疗组的总胃肠道转运时间（TGTT）更长。
TMP-SMX与ATV联合给药显著增加了大鼠体内ATV的暴露量。这种增加可能是由于TGTT延长导致ATV在肠道内停留时间增加，有利于其吸收。TMP-SMX诱导的肠道微生物群变化可能是TGTT延长的原因。如果在人体中得到证实，这种潜在的相互作用可能会伴随着ATV不良反应的增加。
