Effect of Valproate on the Pharmacokinetics and Pharmacodynamics of Lorazepam

Samara, Emil; Granneman, R.; Witt, Galen; Cavanaugh, John H.

doi:10.1002/j.1552-4604.1997.tb04322.x

Cited by 51 publications

(27 citation statements)

References 12 publications

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“…For example, CBZ and PHT, both potent inducers of CYP3A4, decrease the plasma concentration of midazolam (MDL), (129) whereas VPA increases the plasma concentration of lorazepam (LZP) by inhibiting UGT activity (130,131).…”

Section: Psychotropic Drugsmentioning

confidence: 99%

The Importance of Drug Interactions in Epilepsy Therapy

et al. 2002

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Summary: Long-term antiepileptic drug (AED) therapy is the reality for the majority of patients diagnosed with epilepsy. One AED will usually be sufficient to control seizures effectively, but a significant proportion of patients will need to receive a multiple AED regimen. Furthermore, polytherapy may be necessary for the treatment of concomitant disease. The fact that over-the-counter drugs and nutritional supplements are increasingly being self-administered by patients also must be considered. Therefore the probability of patients with epilepsy experiencing drug interactions is high, particularly with the traditional AEDs, which are highly prone to drug interactions. Physicians prescribing AEDs to patients with epilepsy must, therefore, be aware of the potential for drug interactions and the effects (pharmacokinetic and pharmacodynamic) that can occur both during combination therapy and on drug discontinuation. Although pharmacokinetic interactions are numerous and well described, pharmacodynamic interactions are few and usually concluded by default. Perhaps the most clinically significant pharmacodynamic interaction is that of lamotrigine (LTG) and valproic acid (VPA); these drugs exhibit synergistic efficacy when coadministered in patients with refractory partial and generalised seizures. Hepatic metabolism is often the target for pharmacokinetic drug interactions, and enzyme-inducing drugs such as phenytoin (PHT), phenobarbitone (PB), and carbamazepine (CBZ) will readily enhance the metabolism of other AEDs [e.g., LTG, topiramate (TPM), and tiagabine (TGB)].The enzyme-inducing AEDs also enhance the metabolism of many other drugs (e.g., oral contraceptives, antidepressants, and warfarin) so that therapeutic efficacy of coadministered drugs is lost unless the dosage is increased. VPA inhibits the metabolism of PB and LTG, resulting in an elevation in the plasma concentrations of the inhibited drugs and consequently an increased risk of toxicity. The inhibition of the metabolism of CBZ by VPA results in an elevation of the metabolite CBZepoxide, which also increases the risk of toxicity. Other examples include the inhibition of PHT and CBZ metabolism by cimetidine and CBZ metabolism by erythromycin. In recent years, a more rational approach has been taken with regard to metabolic drug interactions because of our enhanced understanding of the cytochrome P450 system that is responsible for the metabolism of many drugs, including AEDs. The review briefly discusses the mechanisms of drug interactions and then proceeds to highlight some of the more clinically relevant drug interactions between AEDs and between AEDs and non-AEDs. Understanding the fundamental principles that contribute to a drug interaction may help the physician to better anticipate a drug interaction and allow a graded and planned therapeutic response and, therefore, help to enhance the management of patients with epilepsy who may require treatment with polytherapy regimens.

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Section: Psychotropic Drugsmentioning

confidence: 99%

The Importance of Drug Interactions in Epilepsy Therapy

et al. 2002

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“…Four PK studies that compared the combination of valproic acid and lorazepam with lorazepam alone were identified. 9,[17][18][19] The data from those studies are summarized in Table 4.…”

Section: Discussionmentioning

confidence: 99%

“…18 All 4 studies showed that valproic acid cotreatment inhibited the metabolism of lorazepam, as indicated by an observed decrease in either lorazepam glucuronide formation clearance 17,18 or the metabolite AUC ratio. 9,19 With regard to elimination, a decrease in plasma clearance of lorazepam was observed in all 4 studies.…”

Section: Discussionmentioning

confidence: 99%

“…9,19 With regard to elimination, a decrease in plasma clearance of lorazepam was observed in all 4 studies. 9,[17][18][19] Some limitations in the interpretation of data from clinical drug interaction studies deserve mention. For example, in addition to UGT induction or inhibition, formation clearance may also be affected by clearance or AUC of the parent drug and other drug-metabolizing enzymes or transport proteins.…”

Section: Discussionmentioning

confidence: 99%

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Pharmacokinetic Interactions between Valproic Acid and Lorazepam (PIVOtAL Study): A Review of Site-Specific Practices

Tang

Kiang

Ensom

2017

CJHP

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Background: Coadministration of lorazepam and valproic acid is identified by tertiary references as causing a major drug interaction that requires therapy modification and dosage adjustments. The proposed mechanism involves inhibition of lorazepam glucuronidation via direct inhibition of uridine 5′-diphosphate-glucuronosyltransferase enzymes by valproic acid. However, the clinical significance of this interaction is unclear.

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“…When used simultaneously with clonazepam, its clearance can increase by 14% while the clearance of valproate can decrease by 18% [29]. In cases of co-administration with lorazepam, the concentration time of lorazepam was found to increase by 20% and the maximum concentration by 8%; nevertheless, this had no significant impact on the therapeutic effect [30]. The other BDs do not react with valproic acid and may be used provided that clinical efficacy is maintained.…”

Section: Benzodiazepinesmentioning

confidence: 99%

Farmakokinetyczne interakcje międzylekowe w oddziale intensywnej terapii – obserwacje jednoośrodkowe i przegląd piśmiennictwa

Łój¹,

Olender²,

Ślęzak³

et al. 2014

Anaesthesiol Intensive Ther

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Background: Drug-drug interactions constitute a serious health hazard in everyday clinical practice in critically ill patients. Drug-drug interactions may be pharmacokinetic or pharmacodynamic in their nature. We aimed to investigate the quantity and quality of possible drug-drug interactions, and their possible side effects in intensive care unit patients in a 12-month period. Methods: This retrospective study covered data on pharmacological treatment of 43 consecutive patients (11 females, 32 males) aged 62 ± 15 years, hospitalized between January 2015 and February 2016. Pharmacokinetic DDIs were identified and graded. Only severe and clinically important drug-drug interactions were subjected for further analysis. Results: Median baseline SAPS III was 53 (IQR 38-67) points. Median intensive care unit stay was 12 (6-25) days. Subjects were treated with a median number of 22 (12-27) drugs. We identified 27 (16-41) possible drug-drug interactions per patient, including 3 (1-7) drug-drug interactions of a severe grade. The total number of severe and clinically important drug-drug interactions was 253 of which 227 were analyzed in detail. No possible side-effects of drug-drug interactions were identified. Conclusions: DDIs as well as their side-effects are challenging regarding their precise evaluation, especially due to the need for multidrug treatment in critically ill patients. Concentration-controlled therapy should be recommended, especially for treatment with vancomycin, digoxin and valproate. Pantoprazole should be a proton pump-inhibitor of choice. Drug dose modification is necessary in combined treatment with fluconazole and amiodarone or rifampicin. From a clinical point of view, the most important impact of drug-drug interactions is on antibiotic treatment effectiveness, especially with meropenem when valproate is also prescribed.

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Effect of Valproate on the Pharmacokinetics and Pharmacodynamics of Lorazepam

Cited by 51 publications

References 12 publications

The Importance of Drug Interactions in Epilepsy Therapy

The Importance of Drug Interactions in Epilepsy Therapy

Pharmacokinetic Interactions between Valproic Acid and Lorazepam (PIVOtAL Study): A Review of Site-Specific Practices

Farmakokinetyczne interakcje międzylekowe w oddziale intensywnej terapii – obserwacje jednoośrodkowe i przegląd piśmiennictwa

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