Dataset Information

In vitro assessment of the potential for dolutegravir to affect hepatic clearance of levonorgestrel.

ABSTRACT:

Objectives

The World Health Organization recommends that all countries adopt dolutegravir-based antiretroviral therapy as the preferred regimen for all individuals living with HIV. Levonorgestrel is a commonly used hormonal contraceptive, which undergoes drug-drug interactions with some antiretrovirals, but the potential interaction between dolutegravir and levonorgestrel has not been examined. We aimed to evaluate cytochrome P450 (CYP)-mediated levonorgestrel metabolism and quantify the effects of dolutegravir on levonorgestrel apparent intrinsic clearance (CL_int.app. ) and CYP gene expression.

Methods

In vitro CYP-mediated CL_int.app. of levonorgestrel was quantified using a recombinant human CYP (rhCYP) enzyme system. A primary human hepatocyte model of drug metabolism was used to assess the effects of dolutegravir on (1) levonorgestrel CL_int.app. , using liquid chromatography-tandem mass spectrometry, and (2) the expression of specific CYP enzymes, using quantitative real-time polymerase chain reaction.

Results

Levonorgestrel clearance was mediated by multiple rhCYPs, including rhCYP3A4. Under control conditions, levonorgestrel CL_int.app. was 22.4 ± 5.0 μL/min/10⁶ hepatocytes. Incubation with 43.1 nM of unbound dolutegravir elevated levonorgestrel CL_int.app. to 31.4 ± 7.8 µL/min/10⁶ hepatocytes (P = 0.168), while 142.23 nM increased levonorgestrel CL_int.app. to 37.0 ± 2.9 µL/min/10⁶ hepatocytes (P = 0.012). Unbound dolutegravir ≥ 431 nM induced expression of CYP3A4 (≥ two-fold) in a dose-dependent manner, while 1.44 μM of unbound dolutegravir induced CYP2B6 expression 2.2 ± 0.3-fold (P = 0.0004).

Conclusions

In summary, this in vitro study suggests that dolutegravir has the potential to increase hepatic clearance of levonorgestrel by inducing both CYP3A and non-CYP3A enzymes. The observed in vitro dolutegravir-levonorgestrel drug-drug interaction should be further examined in clinical studies.

SUBMITTER: Roberts O

PROVIDER: S-EPMC9363158 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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Publications

In vitro assessment of the potential for dolutegravir to affect hepatic clearance of levonorgestrel.

Roberts Owain O Kinvig Hannah H Owen Andrew A Lamorde Mohammed M Siccardi Marco M Scarsi Kimberly K KK

HIV medicine 20210730 10

<h4>Objectives</h4>The World Health Organization recommends that all countries adopt dolutegravir-based antiretroviral therapy as the preferred regimen for all individuals living with HIV. Levonorgestrel is a commonly used hormonal contraceptive, which undergoes drug-drug interactions with some antiretrovirals, but the potential interaction between dolutegravir and levonorgestrel has not been examined. We aimed to evaluate cytochrome P450 (CYP)-mediated levonorgestrel metabolism and quantify the ...[more]

PMID: 34328253

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Dataset Information

In vitro assessment of the potential for dolutegravir to affect hepatic clearance of levonorgestrel.

Objectives

Methods

Results

Conclusions

Publications

In vitro assessment of the potential for dolutegravir to affect hepatic clearance of levonorgestrel.

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