Clinical Consequences of the Biphasic Elimination Kinetics for the Diuretic Effect of Furosemide and its Acyl Glucuronide in Humans

Vree, T. B.; André, J. A. M. Van Der Ven

doi:10.1211/0022357991772402

Cited by 21 publications

(10 citation statements)

References 74 publications

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“…The pharmacokinetics of furosemide is well documented in healthy subjects. Adsorption is rapid and peak levels occur after 60-90 min post-dose and are eliminated by liver and kidney [6]. However, the fast and accurate monitoring of furosemide in bio fluids is important not only in the clinical practice by treatment of patience but also in the field of doping control [7,8].…”

Section: Introductionmentioning

confidence: 99%

Computer aided-molecular design and synthesis of a high selective molecularly imprinted polymer for solid-phase extraction of furosemide from human plasma

Gholivand

Khodadadian

Ahmadi

2010

Analytica Chimica Acta

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Section: Introductionmentioning

confidence: 99%

Computer aided-molecular design and synthesis of a high selective molecularly imprinted polymer for solid-phase extraction of furosemide from human plasma

Gholivand

Khodadadian

Ahmadi

2010

Analytica Chimica Acta

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“…This might be due to enterohepatic recirculation of CRA13 because drugs subject to enterohepatic recirculation are often characterized by multiple peaks and a long half-life (e.g., estradiol) (Vree and Timmer, 1998). Likewise, compounds of many other classes such as sulfonamide diuretics (Vree and van der Ven, 1999), antiarrhythmic drugs (Freedman and Somberg, 1991), or nonsteroidal anti-inflammatory drugs (Busch et al, 1995) are also subjected to enterohepatic recirculation. In addition, the bile salts, released after meal ingestion, could have facilitated further dissolution and solubilization of CRA13 [solubility in water, ϳ0.001-0.002 mg/ml; log partition coefficient (log P) ϭ 6.9], allowing a second absorption phase.…”

Section: Discussionmentioning

confidence: 99%

Cannabinoid Receptor Agonist 13, a Novel Cannabinoid Agonist: First in Human Pharmacokinetics and Safety

Gardin¹,

Kucher²,

Kiese³

et al. 2009

Drug Metab Dispos

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ABSTRACT:Cannabinoid receptor agonist 13 (CRA13) is a novel cannabinoid (CB) receptor agonist with high affinity and functional activity toward both CB 1 and CB 2 receptors. This phase I study aimed to evaluate the pharmacokinetics, safety, and tolerability of single oral doses of CRA13. Sixty-three of 69 healthy adult males were randomized in seven cohorts (n ‫؍‬ 9) to receive 1 to 80 mg of CRA13 or placebo orally in fasted condition. To investigate the diet effect, an independent group (n ‫؍‬ 6) was randomized to receive 40 mg of CRA13 after high-fat and high-calorie breakfast in crossover design with a 2-week washout period. Peak plasma concentration (C max ) ranged from 7.8 to 467.6 ng/ml (1-80 mg). CRA13 was rapidly absorbed and demonstrated linear pharmacokinetics (1-80 mg). Time to reach C max (t max ) was 1.5 to 2 h for all doses in both fasted and fed groups. Administration of 40 mg of CRA13 with food induced approximately 2-fold increase in the C max and the area under the concentration-time curve, AUC 0 ؊ tz . The apparent elimination half-life (t 1/2 ) was 21 to 36 h and 30 to 41 h for fasted and fed groups, respectively. Dizziness, headache, and nausea were the most frequently reported adverse events (AEs), predominantly at the 40-and 80-mg doses. The incidence of AEs was dose-dependent and mild to moderate. No deaths and serious adverse events were reported. In conclusion, CRA13 was reasonably well tolerated and demonstrated a linear pharmacokinetics over the studied dose range (1-80 mg). Food intake increased CRA13 C max and AUC 0 ؊ tz by approximately 2-fold, whereas t max was unaffected.Cannabinoid receptor agonist 13 (CRA13) is a novel cannabinoid (CB) receptor agonist with high affinity and functional activity toward both CB 1 and CB 2 receptors (Dziadulewicz et al., 2007). Cannabis extracts contain a mixture of psychoactive, highly brain-penetrant cannabinoids, structurally related to the major active constituent ⌬ 9 -tetrahydrocannabinol (Fig. 1). In animals, cannabinoids are known to produce a range of well established effects including analgesia, catalepsy, reduced locomotor activity, and hypothermia. These effects are mediated through the activation of CB 1 and CB 2 receptors, both of which are G-protein-coupled and exert their effects predominantly via inhibition of adenylate cyclase (Pertwee and Ross, 2002). Published literature indicates that CB agonists may also be effective against persistent nociceptive processes in clinical conditions associated with chronic pain states (Richardson, 2000;Fox et al., 2001;Pertwee, 2001; Rice, 2001;Karst et al., 2003;Notcutt et al., 2004;Svendsen et al., 2004).Selective activation of peripheral CB 1 receptors could evolve as a valuable therapy for chronic pain conditions as long as the central nervous system (CNS) effects are suppressed. CRA13, in behavioral animal models (rat and guinea pig) of chronic pain (neuropathic and nociceptive), was able to reverse established mechanical hyperalgesia after both oral administration and local injection into h...

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“…Despite this, little is known about the mechanisms of FS-induced liver injury. It has been shown that the major metabolic pathway for elimination of FS in both humans and rodents is glucuronidation (Vree and van der Ven, 1999; Williams et al, 2007). Furthermore, FS appears to be metabolized by cytochrome P450s to an epoxide intermediate (Williams et al, 2007) that reacts with proteins in the liver (Mitchell et al, 1974; 1976; Williams et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

The role of the c-Jun N-terminal kinases 1/2 and receptor-interacting protein kinase 3 in furosemide-induced liver injury

McGill

Xie

et al. 2014

Xenobiotica

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The mechanisms of furosemide (FS) hepatotoxicity were explored in mice. Specifically, C57Bl/6J mice were treated with 500 mg FS / kg bodyweight and c-Jun N-terminal kinase (JNK) activation and RIP3 expression were measured by western blotting. Co-treatment with furosemide and the JNK inhibitor SP600125 was also performed, and FS-induced liver injury was compared in wild-type and RIP3 knockout (KO) mice. JNK phosphorylation and RIP3 expression were increased in livers from the FS-treated mice as early as 6 h after treatment, and persisted until at least 24 h. JNK phosphorylation was also observed in primary mouse hepatocytes and human HepaRG cells treated with FS. Phosphorylated JNK translocated into mitochondria in livers, but no evidence of mitochondrial damage was observed. SP600125 treated mice, SP600125 co-treated primary mouse hepatocytes, and RIP3 KO mice were not protected against FS hepatotoxicity. These data show that, although JNK activation and RIP3 expression are induced by FS, neither contributes to the liver injury.

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Clinical Consequences of the Biphasic Elimination Kinetics for the Diuretic Effect of Furosemide and its Acyl Glucuronide in Humans

Cited by 21 publications

References 74 publications

Computer aided-molecular design and synthesis of a high selective molecularly imprinted polymer for solid-phase extraction of furosemide from human plasma

Computer aided-molecular design and synthesis of a high selective molecularly imprinted polymer for solid-phase extraction of furosemide from human plasma

Cannabinoid Receptor Agonist 13, a Novel Cannabinoid Agonist: First in Human Pharmacokinetics and Safety

The role of the c-Jun N-terminal kinases 1/2 and receptor-interacting protein kinase 3 in furosemide-induced liver injury

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