Kinetic disposition of lorazepam with focus on the glucuronidation capacity, transplacental transfer in parturients and racemization in biological samples

Papini, Olga; Cunha, Sérgio Pereira da; Mathes, Ângelo do Carmo da Silva; Bertucci, Carlo; Moisés, Elaine Christine Dantas; Duarte, Luciana de Barros; Cavalli, Ricardo de Carvalho; Lanchote, Vera Lúcia

doi:10.1016/j.jpba.2005.07.021

Cited by 23 publications

(13 citation statements)

References 28 publications

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“…As DHA is metabolized through hepatic glucuronidation by UGT1A9 and UGT2B7 [12], induction of these enzymes could result in accelerated DHA clearance. Induction of hepatic glucuronidation, potentially by elevated sex hormone levels in pregnancy, may be responsible for the substantial pregnancy-related increases in glucuronidation observed for various drugs, including lamotrigine [24,25], oxcarbazepine [26], and lorazepam [27]. Alterations in hepatic blood flow could also produce changes in DHA clearance.…”

Section: Discussionmentioning

confidence: 99%

Population pharmacokinetics of artesunate and dihydroartemisinin in pregnant and non-pregnant women with malaria

Morris

Onyamboko

Capparelli

et al. 2011

Malar J

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BackgroundThe World Health Organization endorses the use of artemisinin-based combination therapy for treatment of acute uncomplicated falciparum malaria in the second and third trimesters of pregnancy. However, the effects of pregnancy on the pharmacokinetics of artemisinin derivatives, such as artesunate (AS), are poorly understood. In this analysis, the population pharmacokinetics of oral AS, and its active metabolite dihydroartemisinin (DHA), were studied in pregnant and non-pregnant women at the Kingasani Maternity Clinic in the DRC.MethodsData were obtained from 26 pregnant women in the second (22 - 26 weeks) or the third (32 - 36 weeks) trimester of pregnancy and from 25 non-pregnant female controls. All subjects received 200 mg AS. Plasma AS and DHA were measured using a validated LC-MS method. Estimates for pharmacokinetic and variability parameters were obtained through nonlinear mixed effects modelling.ResultsA simultaneous parent-metabolite model was developed consisting of mixed zero-order, lagged first-order absorption of AS, a one-compartment model for AS, and a one-compartment model for DHA. Complete conversion of AS to DHA was assumed. The model displayed satisfactory goodness-of-fit, stability, and predictive ability. Apparent clearance (CL/F) and volume of distribution (V/F) estimates, with 95% bootstrap confidence intervals, were as follows: 195 L (139-285 L) for AS V/F, 895 L/h (788-1045 L/h) for AS CL/F, 91.4 L (78.5-109 L) for DHA V/F, and 64.0 L/h (55.1-75.2 L/h) for DHA CL/F. The effect of pregnancy on DHA CL/F was determined to be significant, with a pregnancy-associated increase in DHA CL/F of 42.3% (19.7 - 72.3%).ConclusionsIn this analysis, pharmacokinetic modelling suggests that pregnant women have accelerated DHA clearance compared to non-pregnant women receiving orally administered AS. These findings, in conjunction with a previous non-compartmental analysis of the modelled data, provide further evidence that higher AS doses would be required to maintain similar DHA levels in pregnant women as achieved in non-pregnant controls.

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Section: Discussionmentioning

confidence: 99%

Population pharmacokinetics of artesunate and dihydroartemisinin in pregnant and non-pregnant women with malaria

Morris

Onyamboko

Capparelli

et al. 2011

Malar J

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“…Lorazepam is currently one of the most frequently used BZDs in clinical settings [41]. Clinicians prefer BZD with an intermediate halflife to extensively sedating long half-life BZDs [42,43]. Lorazepam has been reported to impair motoric function in humans [8] and mice [11].…”

Section: Bzd Injection and Motoric Testmentioning

confidence: 99%

Purkinje-neuron-specific down-regulation of p38 protects motoric function from the repeated use of benzodiazepine

Jung¹,

Metzger²

2013

ABB

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Benzodiazepine (BZD) is the most prescribed CNS depressant in America to treat hyper-excitatory disorders such as anxiety and insomnia. However, the chronic use of BZD often creates adverse effects including psychomotor deficit. In this study, we investigated a novel mechanism by which chronic BZD impedes motoric function in female mice. We used female mice because BZD use is much more prevalent in female than male populations. We tested the hypothesis that the accumulation of p38 (stress-activated protein) in cerebellar Purkinje neurons mediates motoric deficit induced by chronic BZD. To test this hypothesis, we generated transgenic mice that lack p38 in cerebellar Purkinje neurons by crossing Pcp2 (Purkinje cell protein 2)-Cre mice with p38 loxP/loxP mice. p38-knockdown mice and wild-type mice received BZD (lorazepam, 0.5 mg/kg) for 14 days. During this period, they were tested for motoric performance using Rotarod assay in which a quicker fall from rotating rod indicates poorer motoric performance. Cerebellum was then collected to detect p38 in Purkinje neurons and to measure mitochondrial respiration using immunohistochemistry and real-time XF respirometry, respectively. Compared to vehicletreated mice, BZD-treated mice showed poorer motoric performance, a higher number of Purkinje neurons containing p38, and lower mitochondrial respiration. These effects of BZD were much smaller in p38-knockdown mice. These results suggest that the excessive accumulation of p38 in cerebellar Purkinje neurons contributes to motoric deficit associated with chronic BZD. They also suggest that Purkinje neuronal p38 mediates BZD-induced mitochondrial respiratory inhibition in cerebellum. Our findings may provide a new mechanistic insight into chronic BZD-induced motoric deficit.

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“…To make in vivo study more clearly to the readers one experimental methodology used by Papini et al 98 is summarized in this paragraph briefly. The authors selected 10 healthy parturients aged 18-37 yr with a gestational age of 36-40.1 wk and treated with single oral dose of 2.0 mg racemic lorazepam 2 to 9 h before delivery.…”

Section: [(S)-stp] After Oral Administration Of [(S)-stp] But With Amentioning

confidence: 99%

“…The authors also reported that no exposed fetus was free from skeletal defects. Papini et al 98 studied the pharmacokinetic racemization of lorazepam in pregnant women and data given in Table 5 about phamacokinetics of lorazepam and its metabolite (lorazepam-glucuronide) in pregnant women indicate racemization process. Similarly, Pham-Huy et al 99 reported racemization of lorazepam in polar media.…”

Section: In Vivo Racemizationmentioning

confidence: 99%

Role of racemization in optically active drugs development

et al. 2007

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U.S. Food and Drug Administration issues certain guidelines for marketing of optically active drugs as some enantiomers racemize into human body, leading to the generation of other antipodes, which may be toxic or ballast to the human beings. Moreover, racemization reduces the administrated dosage concentration as optically active enantiomer converted into its inactive counter part. Therefore, the study of racemization of such type of drugs is an important and urgent need of today. This article describes in vitro and in vivo racemization of optically active drugs. The racemization process of various optically active drugs has been discussed considering the effect of different variables i.e. pH, temperature, concentration of the drug, ionic concentration, etc. Attempts have also been made to discuss the mechanisms of racemization. Besides, efforts have been made to suggest the safe dosages of such type of drugs too.

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Kinetic disposition of lorazepam with focus on the glucuronidation capacity, transplacental transfer in parturients and racemization in biological samples

Cited by 23 publications

References 28 publications

Population pharmacokinetics of artesunate and dihydroartemisinin in pregnant and non-pregnant women with malaria

Population pharmacokinetics of artesunate and dihydroartemisinin in pregnant and non-pregnant women with malaria

Purkinje-neuron-specific down-regulation of p38 protects motoric function from the repeated use of benzodiazepine

Role of racemization in optically active drugs development

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