Effect of the genotype on the pharmacokinetics, pharmacodynamics, and drug interactions of intravenous lorazepam in healthy volunteers

Chung, Jae‐Yong; Cho, Joo Youn; Yu, Kyung‐Sang; Kim, Jung-Ryul; Jung, Heechul; Lim, Keon-Hee; Jang, In‐Jin; Shin, Sang‐Goo

doi:10.1016/j.clpt.2005.02.006

Cited by 93 publications

(65 citation statements)

References 18 publications

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“…Hepatic expression of UGT shows little interindividual variation, as opposed to the high interindividual variability found in the gastrointestinal tract (Strassburg et al, 1998(Strassburg et al, , 2000, further accentuated by the differential enzyme expression within different segments of the gastrointestinal tract (Strassburg et al, 1998(Strassburg et al, , 2000Antonio et al, 2003;Basu et al, 2004). Genetic polymorphisms have been described for several UGT, and some of them have been associated with interindividual variations in drug effect (Chung et al, 2005) and toxicity (Marsh and McLeod, 2004;Massacesi et al, 2006). Therefore, the identification of specific enzymes involved in the metabolism of a drug is important.…”

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confidence: 99%

Human Metabolism of Nebicapone (BIA 3-202), a Novel Catechol-O-Methyltransferase Inhibitor: Characterization of in Vitro Glucuronidation

Loureiro

Bonifácio²,

Fernandes-Lopes³

et al. 2006

Drug Metab Dispos

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ABSTRACT:Nebicapone (BIA 3-202; 1-[3,4-dihydroxy-5-nitrophenyl]-2-phenylethanone), a novel catechol-O-methyltransferase inhibitor, is mainly metabolized by glucuronidation. The purpose of this study was to characterize the major plasma metabolites of nebicapone following p.o. administration of nebicapone to healthy volunteers, and to determine the human UDP-glucuronosyltransferase (UGT) enzymes involved in nebicapone glucuronidation. Plasma samples were collected as part of a clinical trial at different time points postdose and were analyzed for nebicapone and its metabolites using a validated method consisting of a solid-phase extraction, followed by high-performance liquid chromatography/mass spectrometry detection. The primary metabolic pathways of nebicapone in humans involve mainly 3-O-glucuronidation, the major early metabolite, and 3-O-methylation, the predominant late metabolite. Of the nine commercially available recombinant UGT enzymes studied (UGT1A1, UGT1A3, UGT1A6, UGT1A7, UGT1A8, UGT1A9, UGT1A10, UGT2B7, and UGT2B15), only UGT1A9 exhibited high nebicapone glucuronosyltransferase specific activity (24.3 ؎ 1.3 nmol/mg protein/min). UGT1A6, UGT1A7, UGT1A8, UGT1A10, UGT2B7, and UGT2B15 exhibited low activity (0.1-1.1 nmol/mg protein/min), and UGT1A1 and UGT1A3 showed extremely low activities (less than 0.03 nmol/mg protein/min). The results show that nebicapone is mainly glucuronidated in humans and that multiple UGT enzymes are involved in this reaction.L-3,4-dihydroxyphenylalanine (L-DOPA) therapy has revolutionized treatment of idiopathic Parkinson's disease (PD) by providing a p.o. administered source of dopamine precursor with ready access to the brain, and it remains the most widely used palliative drug for PD. However, L-DOPA is metabolized in the periphery by aromatic Lamino acid decarboxylase (AADC) and catechol-O-methyltransferase (COMT) enzymes, reducing brain availability. Therefore, an improvement in L-DOPA therapy is provided by a combination treatment of L-DOPA with an AADC inhibitor plus a COMT inhibitor, effectively increasing its availability to the brain (Backstrom et al., 1989).Second-generation COMT inhibitors entacapone and tolcapone ( Fig. 1) have proven beneficial when used together with L-DOPA and an AADC inhibitor, such as carbidopa or benserazide, in the medical treatment of patients with PD (Dingemanse et al., 1995;Dingemanse, 1997;Heikkinen et al., 2001Heikkinen et al., , 2002. When metabolized, these nitrocatechol derivatives are extensively conjugated, usually undergo direct glucuronidation catalyzed by UDP-glucuronosyltransferases (UGT), and are then rapidly excreted in the urine (Lautala et al., 1997). Additionally, both methylation and sulfation compete with glucuronidation for conjugation of the adjacent phenolic hydroxyls (Lautala et al., 1997). Major metabolites of tolcapone in human plasma are the 3-O-␤-glucuronic acid (ϳ18.6%) and the 3-O-methyl conjugate (ϳ2.1%). In urine, the 3-O-␤-glucuronic conjugates of tolcapone (ϳ13%) and its derivative N-acetyl amino (ϳ5.7...

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confidence: 99%

Human Metabolism of Nebicapone (BIA 3-202), a Novel Catechol-O-Methyltransferase Inhibitor: Characterization of in Vitro Glucuronidation

Loureiro

Bonifácio²,

Fernandes-Lopes³

et al. 2006

Drug Metab Dispos

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“…Rifampin increases clearance of a number of antiretroviral agents via this mechanism (2, 3). Furthermore, rifampin also induces phase II enzymes, such as UDPglucuronosyl transferase, which has been described to act in vitro and in vivo (5,8,21), and therefore has potential to affect the pharmacokinetics of raltegravir.…”

mentioning

confidence: 99%

Effect of Rifampin, a Potent Inducer of Drug-Metabolizing Enzymes, on the Pharmacokinetics of Raltegravir

Wenning

Hanley

Brainard

et al. 2009

Antimicrob Agents Chemother

154

104

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Raltegravir is a human immunodeficiency virus type 1 integrase strand transfer inhibitor that is metabolized by glucuronidation via UGT1A1 and may be affected by inducers of UGT1A1, such as rifampin (rifampicin). Two pharmacokinetic studies were performed in healthy subjects: study 1 examined the effect of administration of 600-mg rifampin once daily on the pharmacokinetics of a single dose of 400-mg raltegravir, and study 2 examined the effect of 600-mg rifampin once daily on the pharmacokinetics of 800-mg raltegravir twice daily compared to 400-mg raltegravir twice daily without rifampin. Raltegravir coadministered with rifampin resulted in lower plasma raltegravir concentrations: in study 1, the geometric mean ratios (GMRs) and 90% confidence intervals (90% CIs) for the plasma raltegravir concentration determined 12 h postdose (C 12 ), area under the concentration-time curve from 0 h to ؕ (AUC 0-ؕ ), and maximum concentration of drug in plasma (C max ) (400-mg raltegravir plus rifampin/400-mg raltegravir) were 0.39 (0.30, 0.51), 0.60 (0.39, 0.91), and 0.62 (0.37, 1.04), respectively. In study 2, the GMRs and 90% CIs for raltegravir C 12 , AUC 0-12 , and C max (800-mg raltegravir plus rifampin/400-mg raltegravir) were 0.47 (0.36, 0.61), 1.27 (0.94, 1.71), and 1.62 (1.12, 2.33), respectively. Doubling the raltegravir dose to 800 mg when coadministered with rifampin therefore compensates for the effect of rifampin on raltegravir exposure (AUC 0-12 ) but does not overcome the effect of rifampin on raltegravir trough concentrations (C 12 ). Coadministration of rifampin and raltegravir is not contraindicated; however, caution should be used, since raltegravir trough concentrations in the presence of rifampin are likely to be at the lower limit of clinical experience.

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“…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. 9,[17][18][19] Some limitations in the interpretation of data from clinical drug interaction studies deserve mention.…”

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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Effect of the genotype on the pharmacokinetics, pharmacodynamics, and drug interactions of intravenous lorazepam in healthy volunteers

Abstract: Our results suggest that the UGT2B15*2 polymorphism is a major determinant of interindividual variability with respect to the pharmacokinetics and pharmacodynamics of lorazepam.

Cited by 93 publications

References 18 publications

Human Metabolism of Nebicapone (BIA 3-202), a Novel Catechol-O-Methyltransferase Inhibitor: Characterization of in Vitro Glucuronidation

Human Metabolism of Nebicapone (BIA 3-202), a Novel Catechol-O-Methyltransferase Inhibitor: Characterization of in Vitro Glucuronidation

Effect of Rifampin, a Potent Inducer of Drug-Metabolizing Enzymes, on the Pharmacokinetics of Raltegravir

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

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