Review for 10.1186/s12876-020-01532-4 (2021)

Reviewer’s report
Title: 
Overexpression of P-glycoprotein, MRP2, and CYP3A4 impairs intestinal
absorption of octreotide in rats with portal hypertension
Version: 
1 
Date: 
20 Jun 2019
Reviewer: 
Ying-Ying Yang
Reviewer's report:
Comments to the BMGE-D-18-00745
Portal hypertension (PH) is the main cause of complications and death in liver
cirrhosis. Oral administration of octreotide (OCT), a drug that reduces PH by
constricting mesenteric arteries, is limited by marked intestinal first-pass
elimination. In this study, bile duct ligation (BDL) was used in rats to induce
liver cirrhosis with PH to examine the kinetics and molecular determinants of
intestinal absorption of OCT. Through both in situ and in vitro experiments in
jejunal segments, we observed that intestinal OCT absorption in both control and
PH rats is largely determined by Pglycoprotein (P-gp) and, to a lesser extent, by
multidrug resistance-associated protein 2 (MRP2). OCT transportation mediated
by P-gp and MRP2 was proved by Caco-2 cell experiment. The results of RT-
PCR, western blot, and immunohistochemical analyses suggested impaired
absorption of OCT in PH is determined in part by jejuna upregulation of these
two transporters. Using intestinal microsomes, we also found that cytochrome
P450 3A4 metabolizes OCT, and its upregulation in PH likely contributes to
impaired drug absorption. Thus inhibition of P-gp, MRP2, and CYP3A4 may
represent a valid option for decreasing intestinal first-pass effects on orally
administered OCT, thereby increasing its bioavailability to alleviate PH in
patients with cirrhosis. 
Major comments:
The rationales of study 
[1]. In the acute status of variceal bleeding, most patient need to be NPO. In
clinical practice, the intravenous infusion of octreotide needs to give through the
IV pump due to short half-life of octreotide. For chronic use of octreotide, there
is a long acting type of octreotide which call lantreotide. Accordingly, the
rationales to undergone this study need to be clarify. 
-In the "revised" version, authors still did not include previous references about
the rationale of using oral octreotide for decrease PH and prevent variceal
bleeding in cirrhosis. Nonetheless, authors can try to evaluate the effects of
intramuscular administration of octreotide in preventing PH-related complication
in cirrhosis. 
[2].The standard treatment for long-term prophylaxis of the rupture of
esophageal varices is beta-blocker. So, the beta-blocker should be serves as
positive control. 
-It is great that authors plan to do additional experiments in future. 
[3].The background description for mal-aborption of medicine in PH animals is
not clear. Specific references need to be provided. 
-More evidence and rationale for giving long-term oral form of octreotide for
preventing PH-related complication is needed. If authors plan to explore the
possibility of chronic oral administration of octerotide in cirrhotic PH, head to
head comparison with beta-blockers is necessary.
Are the methods appropriate and well described?
If not, please specify what is required in your comments to the authors.
Yes
Does the work include the necessary controls?
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authors.
Yes
Are the conclusions drawn adequately supported by the data shown?
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Unable to assess
Are you able to assess any statistics in the manuscript or would you
recommend an additional statistical review?
If an additional statistical review is recommended, please specify what aspects
require further assessment in your comments to the editors.
Not relevant to this manuscript
Quality of written English
Please indicate the quality of language in the manuscript:
Needs some language corrections before being published
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