Valproic Acid Elimination Rate and Urinary Excretion of Its Glucuronide Conjugate in Patients with Epilepsy.

Yoshida, Hisahiro; Hirozane, Kiyoshi; Kimoto, Hiroo; Hayashi, T.; Akiyama, Tetsuji; Katayama, Hirokazu; Watanabe, Miki; Yoshitomi, Hironori; Kamiya, Akira

doi:10.1248/bpb.22.716

Cited by 5 publications

(2 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These changes are likely to reflect a modification in metabolic drug clearance. In fact, combined HCs are known to induce the microsomal enzymes involved in glucuronide conjugation (3), which contribute to an important extent to VPA metabolism (10). The reduction in VPA CL/F and CL u /F values during the HC‐free interval compared with the period of HC intake can thus be ascribed to deinduction of glucuronosyltransferases after interruption of HC exposure.…”

Section: Discussionmentioning

confidence: 99%

“…The increase in serum VPA concentration during the HC‐free interval ranged from 2% to 38% for total drug and from 15% to 69% for unbound drug, while in a previous case report (8) the increase in total serum VPA levels in a single woman assessed in two different cycles was 159% and 57%, respectively. Such variability may reflect differences in HC doses, formulations and duration of the HC‐free period, differences in functional polymorphisms of glucuronosyltransferases (12) and associated susceptibility to enzyme induction, variation in enzyme deinduction rate during the HC‐free interval, differences in VPA dosage and VPA fraction cleared by conjugation (10), and possibly, HC influences on other pathways involved in VPA metabolism (3). At least in some subjects, HC‐induced changes in VPA concentration may be clinically relevant, as in the woman reported by Herzog et al (8) who had far more frequent seizures during HC intake than during HC‐free periods.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Increased Apparent Oral Clearance of Valproic Acid during Intake of Combined Contraceptive Steroids in Women with Epilepsy

et al. 2006

View full text Add to dashboard Cite

Summary:Purpose: To determine potential changes in total and unbound serum valproic acid (VPA) concentrations at steadystate during a cycle of intake of combined hormonal contraceptive (HC) steroids.Methods: Blood samples were collected from nine women stabilized on VPA monotherapy on two separate randomized occasions: (i) at the end of the 4-to 7-day HC-free interval, and (ii) on the last day of the HC intake period. Trough concentrations of VPA in serum and serum ultrafiltrates were determined by fluorescence polarization immunoassay.Results: In all women, total and unbound VPA concentrations were higher during the HC-free interval than during HC intake (means ± SD: 425 ± 184 vs. 350 ± 145 μmol/L, respectively, for total VPA, p = 0.002, and 55 ± 37 vs. 39 ± 25 μmol/L, respectively, for unbound VPA, p = 0.005). Compared with the HC-free interval, HC intake was associated with a mean 21.5% increase in VPA total apparent oral clearance (from 8.0 ± 5.2 to 9.7 ± 6.4 ml/h/kg, p = 0.01) and a 45.2 % increase in VPA unbound apparent oral clearance (from 79 ± 81 to 115 ± 121 ml/h/kg, p = 0.029).Conclusions: The apparent oral clearance of total and unbound VPA increases during the HC intake period compared with the HC-free interval, probably due to induction of glucuronosyltransferase by ethinylestradiol. The magnitude of the change varies across individuals, being potentially clinically relevant in some cases. Serum VPA concentrations should be monitored when adding or discontinuing HC steroids, and possibly during the on-off intervals of a HC cycle.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Increased Apparent Oral Clearance of Valproic Acid during Intake of Combined Contraceptive Steroids in Women with Epilepsy

et al. 2006

View full text Add to dashboard Cite

show abstract

Drug Bioactivation Covalent Binding to Target Proteins and Toxicity Relevance

Zhou

Chan

Duan

et al. 2005

Drug Metabolism Reviews

251

150

View full text Add to dashboard Cite

A number of therapeutic drugs with different structures and mechanisms of action have been reported to undergo metabolic activation by Phase I or Phase II drug-metabolizing enzymes. The bioactivation gives rise to reactive metabolites/intermediates, which readily confer covalent binding to various target proteins by nucleophilic substitution and/or Schiff's base mechanism. These drugs include analgesics (e.g., acetaminophen), antibacterial agents (e.g., sulfonamides and macrolide antibiotics), anticancer drugs (e.g., irinotecan), antiepileptic drugs (e.g., carbamazepine), anti-HIV agents (e.g., ritonavir), antipsychotics (e.g., clozapine), cardiovascular drugs (e.g., procainamide and hydralazine), immunosupressants (e.g., cyclosporine A), inhalational anesthetics (e.g., halothane), nonsteroidal anti-inflammatory drugs (NSAIDSs) (e.g., diclofenac), and steroids and their receptor modulators (e.g., estrogens and tamoxifen). Some herbal and dietary constituents are also bioactivated to reactive metabolites capable of binding covalently and inactivating cytochrome P450s (CYPs). A number of important target proteins of drugs have been identified by mass spectrometric techniques and proteomic approaches. The covalent binding and formation of drug-protein adducts are generally considered to be related to drug toxicity, and selective protein covalent binding by drug metabolites may lead to selective organ toxicity. However, the mechanisms involved in the protein adduct-induced toxicity are largely undefined, although it has been suggested that drug-protein adducts may cause toxicity either through impairing physiological functions of the modified proteins or through immune-mediated mechanisms. In addition, mechanism-based inhibition of CYPs may result in toxic drug-drug interactions. The clinical consequences of drug bioactivation and covalent binding to proteins are unpredictable, depending on many factors that are associated with the administered drugs and patients. Further studies using proteomic and genomic approaches with high throughput capacity are needed to identify the protein targets of reactive drug metabolites, and to elucidate the structure-activity relationships of drug's covalent binding to proteins and their clinical outcomes.

show abstract

Challenges for Detecting Valproic Acid in a Nontargeted Urine Drug Screening Method

Pope

Black

Drummer

et al. 2017

Therapeutic Drug Monitoring

View full text Add to dashboard Cite

show abstract

Valproic Acid Elimination Rate and Urinary Excretion of Its Glucuronide Conjugate in Patients with Epilepsy.

Cited by 5 publications

References 0 publications

Increased Apparent Oral Clearance of Valproic Acid during Intake of Combined Contraceptive Steroids in Women with Epilepsy

Increased Apparent Oral Clearance of Valproic Acid during Intake of Combined Contraceptive Steroids in Women with Epilepsy

Drug Bioactivation Covalent Binding to Target Proteins and Toxicity Relevance

Challenges for Detecting Valproic Acid in a Nontargeted Urine Drug Screening Method

Contact Info

Product

Resources

About