Interspecies variability and drug interactions of loxapine metabolism in liver microsomes

Abstract

Loxapine is a dibenzoxazepine neuroleptic that is metabolized by the liver in humans. In the present study, we investigated first in vitro loxapine metabolism in liver microsomes from various species including rats, mice, guinea pigs, dogs, rabbits, monkeys and humans. This enables us to choose between species to further validate drug-drug interaction studies. We observed the formation of desmethyl- and hydroxy- metabolites of loxapine after incubation of the different species liver microsomes. Hydroxylation pathway was major in all species. Wide interspecies variability of loxapine metabolism was observed. Loxapine metabolism was similar in human, guinea pig and dog microsomes. We screened in vitro effects of 67 molecules, representative of 8 therapeutic classes, on loxapine metabolism. Loxapine (100 microM) was incubated with guinea pig liver microsomes (1 mg/ml) 30 min at 37 degrees C with and without the presence of interacting drug. We found that most of psychotropics (alimemazine, cyamemazine and levomepromazine), antifungal (ketoconazole), anticancer drugs (daunorubicin, pirarubicin) and analgesic (nefopam) inhibited more than 50% of hydroxyloxapine formation in vitro. Complementary clinical and pharmacokinetic studies should be performed to confirm these results.

The Antipsychotic Drug Loxapine Is an Opener of the Sodium-Activated Potassium Channel Slack (Slo2.2)

“…7-Hydroxyloxapine was found to accumulate in the brain, achieving concentrations as high as 124 ng/g in the striatum, whereas loxapine, amoxapine, and 7-hydroxyamoxapine concentrations were less than 5 ng/g. Despite interspecies variability in loxapine metabolism (Bun et al, 2003), the antipsychotic effects of this drug in humans are more correlated with the plasma levels of its hydroxylated and hydroxylated desmethyl metabolites, rather than the very low parent drug concentrations (Simpson et al, 1978). The maximal plasma concentration after oral administration of 50 mg of loxapine is approximately 30 ng/ml (0.09 M).…”

Multifaceted Factors Causing Conflicting Outcomes in Herb-Drug Interactions

“…For example, liver microsomes, which are widely used in in vitro assay system to evaluate metabolic interactions, do not represent the true in vivo situation because only the endoplasmic reticulum-localized enzymes are contained in liver microsomes, and metabolic interactions via other enzymes cannot be detected [48,50]. The concurrent interaction via transporters and metabolic enzymes are involved in in vivo ADME process, therefore one targeted metabolic enzyme or transporter in in vitro screening is not enough nor even related to the in vivo phenomena [9,31,51]. Furthermore, orally administered ginsenosides affect hepatic CYPs, and their metabolites also alter intestinal P-gp in vivo [52,53].…”

“…Thus, in vivo preclinical systems are necessary to assess HDI outcomes by considering the dispositions of herbal products and drugs (i.e., simultaneous modulation of metabolizing enzymes and transporters by herbal products influencing drug disposition). Although in vivo preclinical studies are important and required to avoid the occurrence of serious adverse reactions of HD combination at clinical levels [46], conflicting outcomes between in vivo preclinical and clinical results still exist [15], due to interspecies variability especially between primates and rodents [51,54]. For example, interspecies variability in metabolizing enzymes [55] and transporters, such as P-gp [55,56] renal organic anion transporters (OATs) and organic cation transporters (OCTs) [57], may contribute to contradictory HDI results [15].…”