Abstract
Nevirapine (NVP) is a first-generation non-nucleoside reverse transcriptase inhibitor widely used for the treatment and prophylaxis of human immunodeficiency virus infection. The drug is taken throughout the patient’s life and, due to the availability of an extended-release formulation, it is administered once daily. This antiretroviral is one of the scarce examples of drugs with prescription criteria based on sex, in order to prevent adverse reactions. The therapy with NVP has been associated with potentially life-threatening liver and idiosyncratic skin toxicity. Multiple evidence has emerged regarding the formation of electrophilic NVP metabolites as crucial for adverse idiosyncratic reactions. The formation of reactive metabolites that yield covalent adducts with proteins has been demonstrated in patients under NVP-based treatment. Interestingly, several pharmacogenetic- and sex-related factors associated with NVP toxicity can be mechanistically explained by an imbalance toward increased formation of NVP-derived reactive metabolites and/or impaired detoxification capability. Moreover, the haptenation of self-proteins by these reactive species provides a plausible link between NVP bioactivation and immunotoxicity, further supporting the relevance of this toxicokinetics hypothesis. In the current paper, we review the existing knowledge and recent developments on NVP metabolism and their relation to NVP toxicity.
| Original language | English |
|---|---|
| Pages (from-to) | 76-90 |
| Number of pages | 15 |
| Journal | Drug Metabolism Reviews |
| Volume | 51 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - 2 Jan 2019 |
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Keywords
- adverse drug reactions
- bioactivation
- drug metabolism
- hepatotoxicity
- Nevirapine
- pharmacogenetics
- protein adducts
- sex-dependent differences
- sulfotransferases
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Singularities of nevirapine metabolism : from sex-dependent differences to idiosyncratic toxicity. / Marinho, Aline T.; Miranda, Joana P.; Caixas, Umbelina; Charneira, Catarina; Gonçalves-Dias, Clara; Marques, M. Matilde; Monteiro, Emília C.; Antunes, Alexandra M.M.; Pereira, Sofia A.
In: Drug Metabolism Reviews, Vol. 51, No. 1, 02.01.2019, p. 76-90.Research output: Contribution to journal › Review article
TY - JOUR
T1 - Singularities of nevirapine metabolism
T2 - from sex-dependent differences to idiosyncratic toxicity
AU - Marinho, Aline T.
AU - Miranda, Joana P.
AU - Caixas, Umbelina
AU - Charneira, Catarina
AU - Gonçalves-Dias, Clara
AU - Marques, M. Matilde
AU - Monteiro, Emília C.
AU - Antunes, Alexandra M.M.
AU - Pereira, Sofia A.
PY - 2019/1/2
Y1 - 2019/1/2
N2 - Nevirapine (NVP) is a first-generation non-nucleoside reverse transcriptase inhibitor widely used for the treatment and prophylaxis of human immunodeficiency virus infection. The drug is taken throughout the patient’s life and, due to the availability of an extended-release formulation, it is administered once daily. This antiretroviral is one of the scarce examples of drugs with prescription criteria based on sex, in order to prevent adverse reactions. The therapy with NVP has been associated with potentially life-threatening liver and idiosyncratic skin toxicity. Multiple evidence has emerged regarding the formation of electrophilic NVP metabolites as crucial for adverse idiosyncratic reactions. The formation of reactive metabolites that yield covalent adducts with proteins has been demonstrated in patients under NVP-based treatment. Interestingly, several pharmacogenetic- and sex-related factors associated with NVP toxicity can be mechanistically explained by an imbalance toward increased formation of NVP-derived reactive metabolites and/or impaired detoxification capability. Moreover, the haptenation of self-proteins by these reactive species provides a plausible link between NVP bioactivation and immunotoxicity, further supporting the relevance of this toxicokinetics hypothesis. In the current paper, we review the existing knowledge and recent developments on NVP metabolism and their relation to NVP toxicity.
AB - Nevirapine (NVP) is a first-generation non-nucleoside reverse transcriptase inhibitor widely used for the treatment and prophylaxis of human immunodeficiency virus infection. The drug is taken throughout the patient’s life and, due to the availability of an extended-release formulation, it is administered once daily. This antiretroviral is one of the scarce examples of drugs with prescription criteria based on sex, in order to prevent adverse reactions. The therapy with NVP has been associated with potentially life-threatening liver and idiosyncratic skin toxicity. Multiple evidence has emerged regarding the formation of electrophilic NVP metabolites as crucial for adverse idiosyncratic reactions. The formation of reactive metabolites that yield covalent adducts with proteins has been demonstrated in patients under NVP-based treatment. Interestingly, several pharmacogenetic- and sex-related factors associated with NVP toxicity can be mechanistically explained by an imbalance toward increased formation of NVP-derived reactive metabolites and/or impaired detoxification capability. Moreover, the haptenation of self-proteins by these reactive species provides a plausible link between NVP bioactivation and immunotoxicity, further supporting the relevance of this toxicokinetics hypothesis. In the current paper, we review the existing knowledge and recent developments on NVP metabolism and their relation to NVP toxicity.
KW - adverse drug reactions
KW - bioactivation
KW - drug metabolism
KW - hepatotoxicity
KW - Nevirapine
KW - pharmacogenetics
KW - protein adducts
KW - sex-dependent differences
KW - sulfotransferases
UR - http://www.scopus.com/inward/record.url?scp=85065761422&partnerID=8YFLogxK
U2 - 10.1080/03602532.2019.1577891
DO - 10.1080/03602532.2019.1577891
M3 - Review article
VL - 51
SP - 76
EP - 90
JO - Drug Metabolism Reviews
JF - Drug Metabolism Reviews
SN - 0360-2532
IS - 1
ER -