HIV-1 Alters Intestinal Expression of Drug Transporters and Metabolic Enzymes: Implications for Antiretroviral Drug Disposition

Kis, Olena; Sankaran-Walters, Sumathi; Hoque, Md. Tozammel; Walmsley, Sharon; Dandekar, Satya; Bendayan, Reina

doi:10.1128/aac.02278-15

Cited by 40 publications

(38 citation statements)

References 46 publications

(79 reference statements)

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“…Preclinical studies in HIV transgenic rats and in viral protein treated cells have demonstrated that HIV viral proteins can alter the expression of a number of ABC transporters (12)(13)(14)(15). These findings are supported by recent clinical studies that demonstrated significant decreases in the protein expression of P-gp and MRP2 in the rectosigmoid colon and MRP2 and BCRP in the intestine of HIV-infected patients as compared to healthy individuals (16,17). Much less is known about the impact of inflammation on renal transporters.…”

Section: Introductionsupporting

confidence: 62%

Endotoxin Modulates the Expression of Renal Drug Transporters in HIV-1 Transgenic Rats

Pour

Piquette-Miller

2018

J Pharm Pharm Sci

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PURPUSE: Bacterial co-infections and low grade endotoxemia are common in HIV patients. Inflammation due to endotoxin or HIV may influence the expression and activity of transporters. Kidney transporters influence renal drug clearances including many antiretroviral agents. Our objective was to study the effect of endotoxin and HIV on the renal expression of drug transporters in an HIV-transgenic (HIV-Tg) rat model. These rats develop immune dysfunction and AIDS-associated conditions like humans. METHODS: Endotoxin or saline was administered intraperitoneally to HIV-Tg or wild type (WT) littermates and kidneys were collected 18 hours later. Expression of transporters and cytokines were measured by qRT-PCR and Western blots. Serum cytokine levels were measured by ELISA. RESULTS: Endotoxin induced serum levels of IL-6, TNF-α and IFN-γ in both HIV-Tg and WT animals. The basal mRNA expression of Oct2, Oct3, Octn1, Mate1, Urat1 and Ent1was significantly lower (33-60%) and the expression of Ent2 and Pept2 was significantly higher (33-45%) in HIV-Tg as compared to WT. While endotoxin significantly downregulated the mRNA expression of Mdra1 and Pept2 in both HIV and WT groups (69-78%), it imposed a significant reduction on the mRNA expression of Oct2, Oct3, Octn1, Mate1, Oat2, urat1, and Ent1 (54-83%) only in the WT group. Endotoxin significantly increased the mRNA expression of Pept1 (140%) in both WT and HIV groups. CONCLUSIONS: HIV and endotoxin each imposed alterations in the expression of many clinically important renal drug transporters although co-infection did not augment this effect. Viral and/or bacterial infections may impact the renal clearance of drug substrates in patients and could potentially be a source of drug-disease interactions.

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Section: Introductionsupporting

confidence: 62%

Endotoxin Modulates the Expression of Renal Drug Transporters in HIV-1 Transgenic Rats

Pour

Piquette-Miller

2018

J Pharm Pharm Sci

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“…Given the patient's long history of nausea/vomiting, in addition to multiple GI surgeries, the overall integrity, function, and motility of his digestive tract may have been compromised. HIV infection itself, particularly during active viral replication and with advanced disease, can contribute to malabsorption, impact barrier function, alter expression of drug‐metabolizing enzymes and uptake/efflux transporters along the intestinal tract, and cause hypochlorhydria that collectively could impact antiretroviral medication absorption.…”

Section: Discussionmentioning

confidence: 99%

Decreased Absorption of Dolutegravir and Tenofovir Disoproxil Fumarate, But Not Emtricitabine, in an HIV‐Infected Patient Following Oral and Jejunostomy‐Tube Administration

et al. 2017

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The use of enteral feeding tubes to administer antiretroviral medication administration is necessary in certain patients with human immunodeficiency virus (HIV) infection. However, adequacy of drug exposures after these administration routes are largely unknown, making dosing recommendations and the attainment of viral suppression challenging in this patient population. This report describes a patient with advanced HIV infection and a complicated medical history, including long-term intractable nausea/vomiting necessitating antiretroviral medication administration via a Roux-en-Y jejunostomy (J)-tube. Pharmacokinetic assessments were performed to compare differences in antiretroviral drug absorption and plasma exposure following oral and J-tube administration of dolutegravir, tenofovir disoproxil fumarate, and emtricitabine. Results were also compared to published pharmacokinetic data in HIV-infected individuals. Exposure to dolutegravir and tenofovir were similar between J-tube and oral administration routes, whereas emtricitabine exposure was 38% lower when administered via J-tube. However, in comparison to reference data in HIV-infected individuals taking these medications orally, exposure to dolutegravir and tenofovir was 75%–76% and 55%–61% lower, respectively, following both routes of administration. Emtricitabine exposure was similar to and 71% higher than reference data following J-tube and oral administration, respectively. This report highlights the importance of performing pharmacokinetic assessments in patients with the potential for impaired drug absorption to ensure antiretroviral treatment success.

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“…164 P-gp and MRP2 protein levels in the rectal-sigmoid colon were lower in antiretroviral-naïve patients compared to non-infected subjects; whether similar expression patterns occur in the liver remains to be evaluated. 165,166 Data quantifying hepatic transporter protein expression followed by subsequent functional studies are needed. Altered ADME processes in clearance organs ( i.e., intestine, liver, and kidney) in combination with the potential for induction by co-medications ( e.g., protease inhibitors) highlights the complexity of predicting transporter-mediated drug disposition in HIV-infected patients.…”

Section: Introductionmentioning

confidence: 99%

Effect of Liver Disease on Hepatic Transporter Expression and Function

Thakkar

Slizgi

Brouwer

2017

Journal of Pharmaceutical Sciences

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Liver disease can alter the disposition of xenobiotics and endogenous substances. Regulatory agencies such as the Food and Drug Administration (FDA) and the European Medicines Evaluation Agency (EMEA) recommend, if possible, studying the effect of liver disease on drugs under development to guide specific dose recommendations in these patients. While extensive research has been conducted to characterize the effect of liver disease on drug-metabolizing enzymes, emerging data have implicated that the expression and/or function of hepatobiliary transport proteins also are altered in liver disease. This review summarizes recent developments in the field, which may have implications for understanding altered disposition, safety, and of efficacy of new and existing drugs. A brief review of liver physiology and hepatic transporter localization/function is provided. Then, the expression and function of hepatic transporters in cholestasis, hepatitis C infection, hepatocellular carcinoma (HCC), human immunodeficiency virus (HIV) infection, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), and primary biliary cirrhosis (PBC) are reviewed. In the absence of clinical data, nonclinical information in animal models is presented. This review aims to advance the understanding of altered expression and function of hepatic transporters in liver disease and the implications of such changes on drug disposition.

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HIV-1 Alters Intestinal Expression of Drug Transporters and Metabolic Enzymes: Implications for Antiretroviral Drug Disposition

Cited by 40 publications

References 46 publications

Endotoxin Modulates the Expression of Renal Drug Transporters in HIV-1 Transgenic Rats

Endotoxin Modulates the Expression of Renal Drug Transporters in HIV-1 Transgenic Rats

Decreased Absorption of Dolutegravir and Tenofovir Disoproxil Fumarate, But Not Emtricitabine, in an HIV‐Infected Patient Following Oral and Jejunostomy‐Tube Administration

Effect of Liver Disease on Hepatic Transporter Expression and Function

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