In Vivo use of the P450 inactivator 1-aminobenzotriazole in the rat: Varied dosing route to elucidate gut and liver contributions to first-pass and systemic clearance

Strelevitz, Timothy J.; Foti, R.; Fisher, Michael B.

doi:10.1002/jps.20538

Cited by 71 publications

(59 citation statements)

References 23 publications

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“…S1) resulted in a high blood clearance of 61 mL/min/kg and a half-life of only 1.3 h. Following predosing of rats with the irreversible CYP450 inhibitor, 1-aminobenzotriazole, the clearance reduced to 31 mL/min/kg. Although these results confirmed a contribution of CYP-metabolism to the clearance of OZ277, they also indicated a role for non-CYP mechanisms, as the reduction in clearance with 1-aminobenzotriazole was considerably less than what would be expected for a compound predominantly cleared through CYP450 metabolism (20,21).…”

Section: Resultsmentioning

confidence: 75%

Synthetic ozonide drug candidate OZ439 offers new hope for a single-dose cure of uncomplicated malaria

Charman

Arbe-Barnes²,

Bathurst

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

341

365

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Ozonide OZ439 is a synthetic peroxide antimalarial drug candidate designed to provide a single-dose oral cure in humans. OZ439 has successfully completed Phase I clinical trials, where it was shown to be safe at doses up to 1,600 mg and is currently undergoing Phase IIa trials in malaria patients. Herein, we describe the discovery of OZ439 and the exceptional antimalarial and pharmacokinetic properties that led to its selection as a clinical drug development candidate. In vitro, OZ439 is fast-acting against all asexual erythrocytic Plasmodium falciparum stages with IC 50 values comparable to those for the clinically used artemisinin derivatives. Unlike all other synthetic peroxides and semisynthetic artemisinin derivatives, OZ439 completely cures Plasmodium berghei -infected mice with a single oral dose of 20 mg/kg and exhibits prophylactic activity superior to that of the benchmark chemoprophylactic agent, mefloquine. Compared with other peroxide-containing antimalarial agents, such as the artemisinin derivatives and the first-generation ozonide OZ277, OZ439 exhibits a substantial increase in the pharmacokinetic half-life and blood concentration versus time profile in three preclinical species. The outstanding efficacy and prolonged blood concentrations of OZ439 are the result of a design strategy that stabilizes the intrinsically unstable pharmacophoric peroxide bond, thereby reducing clearance yet maintaining the necessary Fe(II)-reactivity to elicit parasite death.

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Section: Resultsmentioning

confidence: 75%

Synthetic ozonide drug candidate OZ439 offers new hope for a single-dose cure of uncomplicated malaria

Charman

Arbe-Barnes²,

Bathurst

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

341

365

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“…The BA of midazolam in microminipigs was similar to that in humans, while the CL int values in the other animals were within approximately ± 3-fold that in humans. Hepatic metabolic activities for midazolam in mice, rats, dogs, and monkeys are known to be similar to that in humans, whereas higher intestinal metabolic activities were observed in mice, rats, and monkeys than in humans [11,15,60,62]. CYP3A isoform in mouse, monkey, and pig livers are similar to CYP3A4 in humans with identities (76-95%), and its content of total CYP in dog and monkey livers were similar to that in human liver [4,42,52,63].…”

Section: Discussionmentioning

confidence: 81%

Species Differences in the Pharmacokinetic Parameters of Cytochrome P450 Probe Substrates between Experimental Animals, such as Mice, Rats, Dogs, Monkeys, and Microminipigs, and Humans

S¹

2015

J Drug Metab Toxicol

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To clarify species differences in the pharmacokinetic parameters of cytochrome P450 (CYP) activities between humans and experimental animals, we assessed several CYP activities in mice, rats, dogs, monkeys, and microminipigs, using the simultaneous administration of typical human CYP substrates, such as caffeine (human CYP1A2 substrate), losartan (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6), and midazolam (CYP3A), to these animals. The intrinsic clearance (CL int ) of these 5 substrates was also examined using the liver microsomes of humans and the experimental animals. The high bioavailabilities (BAs) and low CL int values of caffeine in the experimental animals were similar to those in humans. Mice and monkeys had lower BAs and higher CL int values of losartan than those in humans. Mice, rats, and monkeys had lower BAs and higher CL int values of omeprazole than those in humans. The lowest BAs of dextromethorphan were observed in monkeys and microminipigs, and only the CL int in dogs was similar to that in humans. The BA of midazolam in microminipigs only was similar to that in humans, while the CL int values in the other animals were similar to that in humans. These results indicated that in vitro and in vivo experimental data obtained using multiple animals including microminipigs are useful for predicting human pharmacokinetics.

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“…In contrast, the effect of the nonselective P450 inactivator 1-aminobenzotriazole (1 mM) (Caldwell et al, 2005;Strelevitz et al, 2006;Boily et al, 2015;Parrish et al, 2015) on oxidative desulfurization was less severe (rat: t 1/2 from 8.6 to 25 minutes; dog: t 1/2 from 11.0 to 12 minutes (Fig. 7).…”

Section: Resultsmentioning

confidence: 97%

Species Differences in the Oxidative Desulfurization of a Thiouracil-Based Irreversible Myeloperoxidase Inactivator by Flavin-Containing Monooxygenase Enzymes

Eng

Sharma

Wolford

et al. 2016

Drug Metabolism and Disposition

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N1-Substituted-6-arylthiouracils, represented by compound 1 [6-(2,4-dimethoxyphenyl)-1-(2-hydroxyethyl)-2-thioxo-2,3-dihydropyrimidin-4(1H)-one], are a novel class of selective irreversible inhibitors of human myeloperoxidase. The present account is a summary of our in vitro studies on the facile oxidative desulfurization in compound 1 to a cyclic ether metabolite M1 [5-(2,4-dimethoxyphenyl)-2,3-dihydro-7H-oxazolo[3,2-a]pyrimidin-7-one] in NADPH-supplemented rats (t 1/2 [half-life = mean 6 S.D.] = 8.6 6 0.4 minutes) and dog liver microsomes (t 1/2 = 11.2 6 0.4 minutes), but not in human liver microsomes (t 1/2 > 120 minutes). The in vitro metabolic instability also manifested in moderate-to-high plasma clearances of the parent compound in rats and dogs with significant concentrations of M1 detected in circulation. Mild heat deactivation of liver microsomes or coincubation with the flavin-containing monooxygenase (FMO) inhibitor imipramine significantly diminished M1 formation. In contrast, oxidative metabolism of compound 1 to M1 was not inhibited by the pan cytochrome P450 inactivator 1-aminobenzotriazole. Incubations with recombinant FMO isoforms (FMO1, FMO3, and FMO5) revealed that FMO1 principally catalyzed the conversion of compound 1 to M1. FMO1 is not expressed in adult human liver, which rationalizes the species difference in oxidative desulfurization. Oxidation by FMO1 followed Michaelis-Menten kinetics with Michaelis-Menten constant, maximum rate of oxidative desulfurization, and intrinsic clearance values of 209 mM, 20.4 nmol/min/mg protein, and 82.7 ml/min/mg protein, respectively. Addition of excess glutathione essentially eliminated the conversion of compound 1 to M1 in NADPH-supplemented rat and dog liver microsomes, which suggests that the initial FMO1-mediated S-oxygenation of compound 1 yields a sulfenic acid intermediate capable of redox cycling to the parent compound in a glutathionedependent fashion or undergoing further oxidation to a more electrophilic sulfinic acid species that is trapped intramolecularly by the pendant alcohol motif in compound 1.

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In Vivo use of the P450 inactivator 1-aminobenzotriazole in the rat: Varied dosing route to elucidate gut and liver contributions to first-pass and systemic clearance

Cited by 71 publications

References 23 publications

Synthetic ozonide drug candidate OZ439 offers new hope for a single-dose cure of uncomplicated malaria

Synthetic ozonide drug candidate OZ439 offers new hope for a single-dose cure of uncomplicated malaria

Species Differences in the Pharmacokinetic Parameters of Cytochrome P450 Probe Substrates between Experimental Animals, such as Mice, Rats, Dogs, Monkeys, and Microminipigs, and Humans

Species Differences in the Oxidative Desulfurization of a Thiouracil-Based Irreversible Myeloperoxidase Inactivator by Flavin-Containing Monooxygenase Enzymes

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