Drug Transporter and Metabolizing Enzyme Gene Variants and Nonnucleoside Reverse-Transcriptase Inhibitor Hepatotoxicity

Ritchie, Marylyn D.; Haas, David W.; Motsinger, Alison A.; Donahue, John P.; Erdem, Huso; Raffanti, Stephen; Rebeiro, Peter F; George, Alfred L.; Kim, Richard B.; Haines, Jonathan L.

doi:10.1086/507101

Cited by 95 publications

(63 citation statements)

References 13 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Genetic variants in the ABCB1 gene have been reported to be responsible for variable protease inhibitors pharmacokinetics in children [23] and adults [24]. Although neither NVP or EFV are known substrates of ABCB1 [25], several studies have shown clinical associations between ABCB1 genotypes and NNRTIs pharmacokinetics (including EFV) [24], virologic outcomes in patients receiving EFV containing regimens, [26] and the risk of NVP-induced hepatotoxicity [27,28]. Furthermore, ICs of NVP inversely correlate with ABCB1 expression on PBMCs in subjects receiving NVP [19].…”

Section: Discussionmentioning

confidence: 99%

Intracellular Concentrations of Non-Nucleoside Reverse Transcriptase Inhibitors and its Potential Role on Apoptosis in Peripheral Blood Mononuclear Cells

Saitoh¹

2011

J Antivir Antiretrovir

View full text Add to dashboard Cite

Background: Efavirenz (EFV) and nevirapine (NVP) are non-nucleoside reverse transcriptase inhibitors (NNRTIs) that are frequently used in combination with other antiretrovirals for the treatment of HIV-infected persons. Little information is available regarding the intracellular concentrations (ICs) of EFV and NVP in peripheral blood mononuclear cells (PBMCs) and its potential role for cellular toxicity. Methods:PBMCs from healthy adult donors were treated with or without the mean peak steady-state levels (Cmax) of EFV (12.4µM) and NVP (17.0µM) in human plasma during antiretroviral therapy multiplied by 0.5, 1.0, 2.0 and 4.0. After 48 hr treatment, ICs of EFV and NVP were measured using liquid chromatoagraphy-ion trap/mass spectrometry. The degree of apoptotic cells and mitochondrial membrane potential in PBMCs were measured by flow cytometry. Results:The mean log ICs of x1.0 Cmax NVP in PBMCs (2.00 ± 0.23 µM) were significantly lower than the one of x1.0 Cmax EFV (2.95 ± 0.22 µM) (P < 0.01). Similar significant differences of mean log ICs were observed when the concentration of NNRTIs were x0.5 Cmax (1.62 ± 0.26 μM vs. 2.87 ± 0.13 μM, P < 0.01) and x2.0 Cmax (1.99 ± 0.39 μM vs. 3.11 ± 0.21 μM, P < 0.01). Furthermore, apoptotic PBMCs were lower than PBMC treated with the concentrations of NVP above the plasma Cmax observed clinically in patients as compared to those treated with comparable concentrations of EFV (P < 0.01). Conclusion:These in vitro data suggest that ICs of NVP in PBMCs are significantly lower than ICs of EFV in PBMC and are also associated with less apoptotic PBMCs. The clinical relevance of this observation remains to be elucidated. [18,19,20]; however, no study compared the differences in ICs of EFV and NVP using an in vitro model. Materials and Methods Peripheral blood mononuclear cells (PBMCs) isolationPBMCs were obtained from healthy adult donors (n = 5, multiple ethnicities and race) using a Ficoll-Paque (GE Healthcare) density gradient according to the manufacturer's instructions. EFV and NVP treatment of PBMCsIsolated PBMCs were counted and incubated in 3 mL of serum free media (AIM-V, Invitrogen, Carlsbad, CA) at a concentration of 1.0 x 10 6 /mL in 6-well plates (Corning, Corning, NY). EFV was purchased from Morevak Biochemicals (Brea, CA) and NVP was provided by Boehringer Ingelheim (New York, NY). Both compounds were reconstituted in 50% ethanol. The cells were treated with or without the mean peak steady-state levels (Cmax) of EFV and NVP in human plasma during antiretroviral therapy multiplied by 0.5, 1.0, 2.0 and 4.0. The cells were also incubated with vehicle (50% ethanol) with the highest concentration of ethanol (0.78%) used to reconstitute EFV for each assay. The Cmax of EFV and NVP were 12.4μM and 17.0μM, respectively. The cells were treated for 48 hr at 37°C at 5% CO 2 . The assays contained cells treated with each treatment condition in duplicates and were repeated five times using different donor samples. Measurement of intracellular concentrations of EFV and NVP ...

show abstract

Section: Discussionmentioning

confidence: 99%

Intracellular Concentrations of Non-Nucleoside Reverse Transcriptase Inhibitors and its Potential Role on Apoptosis in Peripheral Blood Mononuclear Cells

Saitoh¹

2011

J Antivir Antiretrovir

View full text Add to dashboard Cite

show abstract

“…The polymorphism ABCB1-3435C>T has been associated with a decreased risk of hepatotoxicty in patients receiving NVP [37][38][39]; nevertheless, this observation is paradoxical since a lower expression of P-gp would lead to a greater accumulation of NVP inside the hepatocytes.…”

Section: Cyp2b6-g516gg (Common Genotype)mentioning

confidence: 99%

The Pharmacogenetics of HIV Treatment: A Practical Clinical Approach

Barc¹

2013

J Pharmacogenom Pharmacoproteomics

View full text Add to dashboard Cite

“…Factors associated with hepatotoxicity include female gender, higher baseline and actual CD4 + T-cell counts [47,48], and HLA-DRB1*0101 [49]. Although NVP is not a substrate of P-glycoprotein [50], the ATP binding cassette, subfamily B, member 1 (ABCB1), which encodes P-glycoprotein, the ABCB1-C3435T (rs1045642) genotype has been reported to be associated with the incidence of hepatotoxicity in HIV-1 infected adults receiving NVP containing HAART regimens [51,52]. Richie et al evaluated the possible significant genotypes in 13 patients who developed NVP-associated hepatotoxicity with 49 matched controls [52].…”

Section: Cyp2b6 Genotype and Adverse Effects Associated With Nnrti Usementioning

confidence: 99%

“…Although NVP is not a substrate of P-glycoprotein [50], the ATP binding cassette, subfamily B, member 1 (ABCB1), which encodes P-glycoprotein, the ABCB1-C3435T (rs1045642) genotype has been reported to be associated with the incidence of hepatotoxicity in HIV-1 infected adults receiving NVP containing HAART regimens [51,52]. Richie et al evaluated the possible significant genotypes in 13 patients who developed NVP-associated hepatotoxicity with 49 matched controls [52]. Using univariate analysis, the ABCB1-3435-T allele and the status of hepatitis B surface antigen were associated with a decreased likelihood of hepatotoxicity.…”

Section: Cyp2b6 Genotype and Adverse Effects Associated With Nnrti Usementioning

confidence: 99%

Effect of Host Genetic Variation on the Pharmacokinetics and Clinical Response of Nnrtis

Saitoh

Spector

2007

Future HIV Ther.

View full text Add to dashboard Cite

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) have been used widely for treating human immunodeficiency virus type 1 (HIV-1) infected patients as a component of highly active antiretroviral therapy (HAART) and for the prevention of mother-to-child transmission (MTCT). Cytochrome P450 (CYP) 2B6 is an important hepatic isoenzyme responsible for the metabolism of NNRTIs including efavirenz and nevirapine. Recent pharmacogenetic studies have shown that CYP2B6 genetic variants alter hepatic CYP2B6 protein expression and function, and the pharmacokinetics of several CYP2B6 substrates. In particular, the CYP2B6-G516T polymorphism in exon 4 affects the pharmacokinetics of efavirenz. Other studies have shown associations of the CYP2B6-G516T genotype with nevirapine pharmacokinetics and central nervous system adverse effects related to efavirenz use. In total, CYP2B6 genetic variants are important determinants of efavirenz and nevirapine pharmacokinetics . Further studies are needed to identify the associations of CYP2B6 genetic variants with the development of NNRTI resistant viruses.

show abstract

Drug Transporter and Metabolizing Enzyme Gene Variants and Nonnucleoside Reverse-Transcriptase Inhibitor Hepatotoxicity

Cited by 95 publications

References 13 publications

Intracellular Concentrations of Non-Nucleoside Reverse Transcriptase Inhibitors and its Potential Role on Apoptosis in Peripheral Blood Mononuclear Cells

Intracellular Concentrations of Non-Nucleoside Reverse Transcriptase Inhibitors and its Potential Role on Apoptosis in Peripheral Blood Mononuclear Cells

The Pharmacogenetics of HIV Treatment: A Practical Clinical Approach

Effect of Host Genetic Variation on the Pharmacokinetics and Clinical Response of Nnrtis

Contact Info

Product

Resources

About