A Generalized Seizure Following Initiation of Nelfinavir in a Patient with Human Immunodeficiency Virus Type 1 Infection, Suspected due to Interaction between Nelfinavir and Phenytoin.

Honda, Masashi; Yasuoka, Akira; Aoki, Makoto; Oka, Shinichi

doi:10.2169/internalmedicine.38.302

Cited by 29 publications

(13 citation statements)

References 7 publications

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“…and nelfinavir (750 mg t.i.d.) have been observed to induce the clearance of warfarin (Knoell et al, 1998;Newshan and Tsang, 1999) and phenytoin (Honda et al, 1999;Lim et al, 2004). FIG.…”

Section: Discussionmentioning

confidence: 97%

Cytochrome P450 Enzymes and Transporters Induced by Anti-Human Immunodeficiency Virus Protease Inhibitors in Human Hepatocytes: Implications for Predicting Clinical Drug Interactions

et al. 2007

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ABSTRACT:Although many of the clinically significant drug interactions of the anti-human immunodeficiency virus (HIV) protease inhibitors (PIs) can be explained by their propensity to inactivate CYP3A enzymes, paradoxically these drugs cause (or lack) interactions with CYP3A substrates that cannot be explained by this mechanism (e.g., alprazolam). To better understand these paradoxical interactions (or lack thereof), we determined the cytochromes P450 and transporters induced by various concentrations (0-25 M) of two PIs, ritonavir and nelfinavir, and rifampin (positive control) in primary human hepatocytes. At 10 M, ritonavir and nelfinavir suppressed CYP3A4 activity but induced its transcripts and protein expression (19-and 12-and 12-and 6-fold, respectively; a >2-fold change over control was interpreted as induction). At 10 M, rifampin induced CYP3A4 transcripts, CYP3A protein, and activity by 23-, 12-, and 13-fold, respectively. The induction by rifampin of CYP3A activity was significantly correlated with its induction of CYP3A4 transcripts (r ‫؍‬ 0.96, p < 0.05) and CYP3A protein (r ‫؍‬ 0.89, p < 0.05). All three drugs (10 M) induced CYP2B6 activity by 2-to 4-fold, CYP2C8 and 2C9 activity by 2-to 4-fold and the transcripts of CYP2B6, 2C8, and 2C9 by >3-, 5-, and 3-fold, respectively. CYP2C19 and 1A2 activity and transcripts were modestly induced (2-fold), whereas, as expected, CYP2D6 was not induced by any of the drugs. Of the transporters studied, protease inhibitors moderately induced multidrug resistance 1 (ABCB1) and multidrug resistance-associated protein (ABCC1) transcripts but had no or minimal effect on the transcripts of breast cancer resistance protein (ABCG2), organic anion-transporting peptide (OATP) 1B1 (SLCO1B1), or OATP1B3 (SLCO1B3). On the basis of these data, we concluded that many of the paradoxical drug interactions (or lack thereof) with the PIs are metabolism-rather than transporter-based and are due to induction of CYP2B6 and 2C enzymes.

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“…and nelfinavir (750 mg t.i.d.) have been observed to induce the clearance of warfarin (Knoell et al, 1998;Newshan and Tsang, 1999) and phenytoin (Honda et al, 1999;Lim et al, 2004). FIG.…”

Section: Discussionmentioning

confidence: 97%

Cytochrome P450 Enzymes and Transporters Induced by Anti-Human Immunodeficiency Virus Protease Inhibitors in Human Hepatocytes: Implications for Predicting Clinical Drug Interactions

et al. 2007

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“…In addition, 14 case studies (class IV) described patients whose AED concentrations changed after ARV therapy was initiated (Honda et al., 1999; Berbel Garcia et al., 2000; Burman & Orr, 2000; Hugen et al., 2000; Kato et al., 2000; Mateu‐de Antonio et al., 2001; Robertson et al., 2005; Bates & Herman, 2006; Motoya et al., 2006; Saraga et al., 2006; Bonora et al., 2007). In some cases, this provides some confirmatory patient data supporting the significance of the human volunteer data.…”

Section: Analysis Of the Evidencementioning

confidence: 99%

Antiepileptic drug selection for people with HIV/AIDS: Evidence‐based guidelines from the ILAE and AAN

Birbeck

French²,

Perucca

et al. 2012

Epilepsia

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Summary A joint panel of the American Academy of Neurology (AAN) and the International League Against Epilepsy (ILAE) convened to develop guidelines for selection of antiepileptic drugs (AEDs) among people with HIV/AIDS. The literature was systematically reviewed to assess the global burden of relevant comorbid entities, to determine the number of patients who potentially utilize AEDs and antiretroviral agents (ARVs), and to address AED–ARV interactions. Key findings from this literature search included the following: AED–ARV administration may be indicated in up to 55% of people taking ARVs. Patients receiving phenytoin may require a lopinavir/ritonavir dosage increase of approximately 50% to maintain unchanged serum concentrations (Level C). Patients receiving valproic acid may require a zidovudine dosage reduction to maintain unchanged serum zidovudine concentrations (Level C). Coadministration of valproic acid and efavirenz may not require efavirenz dosage adjustment (Level C). Patients receiving ritonavir/atazanavir may require a lamotrigine dosage increase of approximately 50% to maintain unchanged lamotrigine serum concentrations (Level C). Coadministration of raltegravir/atazanavir and lamotrigine may not require lamotrigine dosage adjustment (Level C). Coadministration of raltegravir and midazolam may not require midazolam dosage adjustment (Level C). Patients may be counseled that it is unclear whether dosage adjustment is necessary when other AEDs and ARVs are combined (Level U). It may be important to avoid enzyme‐inducing AEDs in people on ARV regimens that include protease inhibitors or nonnucleoside reverse transcriptase inhibitors because pharmacokinetic interactions may result in virologic failure, which has clinical implications for disease progression and development of ARV resistance. If such regimens are required for seizure control, patients may be monitored through pharmacokinetic assessments to ensure efficacy of the ARV regimen (Level C).

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“…Lopinavir/ritonavir and nelfinavir have been found to induce the clearance of warfarin [1288][1289][1290][1291][1292] and phenytoin [1293][1294][1295].…”

Section: Anti-hiv Drugsmentioning

confidence: 99%

Substrates, Inducers, Inhibitors and Structure-Activity Relationships of Human Cytochrome P450 2C9 and Implications in Drug Development

Zhou¹,

Zhou²,

Liu³

et al. 2009

CMC

149

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Cytochrome P450 2C9 (CYP2C9) is one of the most abundant CYP enzymes in the human liver. CYP2C9 metabolizes more than 100 therapeutic drugs, including tolbutamide, glyburide, diclofenac, celecoxib, torasemide, phenytoin losartan, and S-warfarin). Some natural and herbal compounds are also metabolized by CYP2C9, probably leading to the formation of toxic metabolites. CYP2C9 also plays a role in the metabolism of several endogenous compounds such as steroids, melatonin, retinoids and arachidonic acid. Many CYP2C9 substrates are weak acids, but CYP2C9 also has the capacity to metabolise neutral, highly lipophilic compounds. A number of ligand-based and homology models of CYP2C9 have been reported and this has provided insights into the binding of ligands to the active site of CYP2C9. Data from the site-directed mutagenesis studies have revealed that a number of residues (e.g. Arg97, Phe110, Val113, Phe114, Arg144, Ser286, Asn289, Asp293 and Phe476) play an important role in ligand binding and determination of substrate specificity. The resolved crystal structures of CYP2C9 have confirmed the importance of these residues in substrate recognition and ligand orientation. CYP2C9 is activated by dapsone and its analogues and R-lansoprazole in a stereo-specific and substrate-dependent manner, probably through binding to the active site and inducing positive cooperativity. CYP2C9 is subject to induction by rifampin, phenobarbital, and dexamethasone, indicating the involvement of pregnane X receptor, constitutive androstane receptor and glucocorticoid receptor in the regulation of CYP2C9. A number of compounds have been found to inhibit CYP2C9 and this may provide an explanation for some clinically important drug interactions. Tienilic acid, suprofen and silybin are mechanism-based inhibitors of CYP2C9. Given the critical role of CYP2C9 in drug metabolism and the presence of polymorphisms, it is important to identify drug candidates as potential substrates, inducer or inhibitors of CYP2C9 in drug development and drug discovery scientists should develop drugs with minimal interactions with this enzyme. Further studies are warranted to explore the molecular determinants for ligand-CYP2C9 binding and the structure-activity relationships.

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A Generalized Seizure Following Initiation of Nelfinavir in a Patient with Human Immunodeficiency Virus Type 1 Infection, Suspected due to Interaction between Nelfinavir and Phenytoin.

Cited by 29 publications

References 7 publications

Cytochrome P450 Enzymes and Transporters Induced by Anti-Human Immunodeficiency Virus Protease Inhibitors in Human Hepatocytes: Implications for Predicting Clinical Drug Interactions

Cytochrome P450 Enzymes and Transporters Induced by Anti-Human Immunodeficiency Virus Protease Inhibitors in Human Hepatocytes: Implications for Predicting Clinical Drug Interactions

Antiepileptic drug selection for people with HIV/AIDS: Evidence‐based guidelines from the ILAE and AAN

Substrates, Inducers, Inhibitors and Structure-Activity Relationships of Human Cytochrome P450 2C9 and Implications in Drug Development

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