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Efavirenz, atazanavir, and ritonavir disrupt sarcoplasmic reticulum Ca²⁺ homeostasis in skeletal muscles.

ABSTRACT: While muscle fatigue, pain and weakness are common co-morbidities in HIV-1 infected people, their underlying cause remain poorly defined. To this end, we evaluated whether the common antiretroviral drugs efavirenz (EFV), atazanavir (ATV) and ritonavir (RTV) could be a contributing factor by pertubating sarcoplasmic reticulum (SR) Ca²⁺ cycling. In live-cell imaging, EFV (6.0 μM), ATV (6.0 μM), and RTV (3.0 μM) elicited Ca²⁺ transients and blebbing of the plasma membranes of C2C12 skeletal muscle myotubes. Pretreating C2C12 skeletal muscle myotubes with the SR Ca²⁺ release channel blocker ryanodine (50 μM), slowed the rate and amplitude of Ca²⁺ release from and reuptake of Ca²⁺ into the SR. EFV, ATV and RTV (1 nM - 20 μM) potentiated and then displaced [³H] ryanodine binding to rabbit skeletal muscle ryanodine receptor Ca²⁺ release channel (RyR1). These drugs at concentrations 0.25-31.2 μM also increased and or decreased the open probability of RyR1 by altering its gating and conductance. ATV (≤5 μM) potentiated and >5μM inhibited the ability of sarco (endo)plasmic reticulum Ca²⁺-ATPase (SERCA1) to hydrolyze ATP and transport Ca²⁺. RTV (2.5-31.5 μM) dose-dependently inhibited SERCA1-mediated, ATP-dependent Ca²⁺ transport. EFV (0.25-31.5 μM) had no measurable effect on SERCA1's ability to hydrolyze ATP and transport Ca²⁺. These data support the notion that EFV, ATV and RTV could be contributing to skeletal muscle co-morbidities in PLWH by modulating SR Ca²⁺ homeostasis.

SUBMITTER: Alomar FA

PROVIDER: S-EPMC8019157 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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Efavirenz, atazanavir, and ritonavir disrupt sarcoplasmic reticulum Ca2+ homeostasis in skeletal muscles.

Alomar Fadhel A FA Tian Chengju C Dash Prasanta K PK McMillan JoEllyn M JM Gendelman Howard E HE Gorantla Santhi S Bidasee Keshore R KR

Antiviral research 20210113

While muscle fatigue, pain and weakness are common co-morbidities in HIV-1 infected people, their underlying cause remain poorly defined. To this end, we evaluated whether the common antiretroviral drugs efavirenz (EFV), atazanavir (ATV) and ritonavir (RTV) could be a contributing factor by pertubating sarcoplasmic reticulum (SR) Ca2+ cycling. In live-cell imaging, EFV (6.0 μM), ATV (6.0 μM), and RTV (3.0 μM) elicited Ca2+ transients and blebbing of the plasma membranes of ...[more]

PMID: 33450312

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Project description:The current study was conducted to determine if efavirenz (EFV) or atazanavir/ritonavir (ATV/r)-based combination antiretroviral therapy (cART) impacted steady-state atovaquone plasma concentrations in human immunodeficiency virus (HIV)-infected patients receiving treatment doses of atovaquone.Thirty HIV-infected volunteers were recruited, 10 taking no cART and 10 each taking cART that included EFV or ATV/r. Subjects were randomly assigned to atovaquone 750 mg twice daily (BID) for 14 days followed by atovaquone 1500 mg BID for 14 days, or vice-versa, with a washout period in between. On day 14 of each phase, blood was sampled for pharmacokinetic studies, and the area under the concentration-time curve (AUC?) and average concentration (C avg) were calculated and compared using an unpaired t test.Twenty-nine subjects completed both dosing cohorts. Subjects receiving EFV-based cART had 47% and 44% lower atovaquone AUC? than subjects not receiving cART at atovaquone doses of 750 mg BID and 1500 mg BID, respectively (P? .01). Only 5 of 10 subjects receiving EFV-based cART plus atovaquone 750 mg BID had an atovaquone C avg>15 µg/mL, which has previously been associated with successful treatment of Pneumocystis jirovecipneumonia. AUC? and Cavg did not significantly differ for concurrent ATV/r for 750 mg BID or 1500 mg BID when compared to the group not receiving cART. Nine of 10 subjects not receiving cART, 8 of 10 subjects receiving ATV/r, and 2 of 10 subjects receiving EFV in combination with atovaquone 750 mg BID achieved an atovaquone C avg>18.5 µg/mL, a concentration that has previously been associated with successful treatment of Toxoplasmaencephalitis (TE).These data suggest that the currently recommended dose of atovaquone 750 mg BID for treatment of mild to moderate PCP may not be adequate in patients receiving concurrent EFV. Furthermore, doses lower than the currently recommended dose of 1500 mg BID may achieve plasma concentrations adequate to treat TE in HIV-infected patients not receiving EFV.NCT01479361.

Dataset Information

Efavirenz, atazanavir, and ritonavir disrupt sarcoplasmic reticulum Ca²⁺ homeostasis in skeletal muscles.

Publications

Efavirenz, atazanavir, and ritonavir disrupt sarcoplasmic reticulum Ca<sup>2+</sup> homeostasis in skeletal muscles.

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