In vitro effects of quinoline derivatives on cytochrome p-450 and aminopyrine n-demethylase activity in rat hepatic microsomes

doi:10.1016/0006-2952(84)90090-X

Biochemical Pharmacology

Volume 33, Issue 20, 15 October 1984, Pages 3277-3281

https://doi.org/10.1016/0006-2952(84)90090-X Get rights and content

Abstract

A series of quinoline drugs was evaluated for the ability to inhibit rat liver microsomal aminopyrine N-demethylase (APDM) activity in vitro. Quinine was found to be a quite potent inhibitor of APDM from control rat liver (I₅₀ = 0.061 mM) but was only approximately half as potent against APDM from phenobarbitone-induced rat liver (I₅₀ = 0.14 mM). Primaquine and amodiaquine were also relatively potent inhibitors of these activities, but quinidine and chloroquine were essentially noninhibitory, especially against control-type APDM. Primaquine and quinine elicited characteristic type II optical difference spectra with oxidised cytochrome P-450 from both types of microsomes whereas chloroquine and quinidine were type IIb ligands for cytochrome P-450 in phenobarbitone-induced microsomal fractions. Good correlations were obtained for the logarithmic relationship between binding affinity (K_s) and inhibition potency (I₅₀), as well as the logarithmic relationship between efficiency of binding (ΔA_max/K_s) and inhibition. These findings suggest that the capacity of quinoline antimalarials, and similar drugs, to inhibit microsomal APDM activity is related to the affinity of the type II spectral binding interaction between the drug and oxidised cytochrome P-450.

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Rats treated with quinoline, and to a lesser extent, isoquinoline (75 mg/kg, daily for 3 days) showed induction of phase II drug metabolizing enzyme activities without inducing either cytochrome P450 concentration or CYP1A-, CYP2B-, CYP2E-, and CYP3A-selective activities. Elevations of UDP-glucuronosyltransferase activities towards 4-nitrophenol, 1-naphthol, and morphine elicited by quinoline (1.9- to 2.7-fold), were greater than those elicited by isoquinoline (1.4- to 1.8-fold). UDP-glucuronosyltransferase activities towards estrone and testosterone were not increased by either compound. Microsomal epoxide hydrolase activity was increased only by quinoline (2.7-fold). NAD(P)H quinone oxidoreductase activity was increased 2-fold by quinoline and isoquinoline. Cytosolic glutathione S-transferase (GST) activity was increased similarly (≈ 20%) by both agents. Similar treatment of rats with either quinine (75 mg/kg) or chloroquine (150 mg/kg) increased 1-naphthol glucuronidation and GST (quinine only) activities. At 75 mg/kg, chloroquine did not affect any phase II enzyme activities but caused a minor elevation of a phase I enzyme, CYP1A; ascertained from an elevation of 7-ethoxyresorufin deethylase activity and a small hypsochromic shift of the absorbance maximum of the cytochrome P450 CO-complex. With quinoline and isoquinoline treatments (n = 14), the correlation coefficients (R) between microsomal epoxide hydrolase and UDP-glucuronosyltransferase activities towards 4-nitrophenol and morphine were 0.96 and 0.92 respectively, suggesting a highly coordinated induction. The highest NAD(P)H quinone oxidoreductase correlations were with microsomal epoxide hydrolase, and UDP-glucuronosyltransferase activities towards 4-nitrophenol and morphine, (R ≈ 0.78). Correlation coefficients between GST and microsomal epoxide hydrolase and NAD(P)H quinone oxidoreductase activities were ≈0.49. Quinoline and isoquinoline, nitrogen heterocyclic analogs of naphthalene, join the list of simple nitrogen-containing polycyclic aromatic agents capable of selective induction of phase II drug metabolizing enzymes. The position of the single heterocyclic nitrogen atom in the bicyclic ring influences the magnitude and breadth of the induction response. The addition of bulky ring substituents (quinine, chloroquine) reduced the induction response.
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The effect of chloroquine (CHQ) administration on antioxidant enzymes in rat liver and kidney was studied. Male Sprague–Dawley rats were administered 20 mg/kg CHQ once a week for 4 weeks (chronic treatment) or a single dose at 10 or 20 mg/kg (acute treatment). Antioxidant enzyme activities were determined in cytosolic fractions of liver and kidney, whereas reduced glutathione (GSH) and malondialdehyde (MDA) were determined in tissue samples. Results indicate minimal effects of acute CHQ treatment, whereas chronic treatment with CHQ differentially affected antioxidant enzymes in the two organs. Superoxide dismutase activity was increased nearly twofold, while activities of selenium glutathione peroxidase (GPX), catalase, and NAD (P) H: quinone oxidoreductase were decreased in livers of CHQ-treated rats compared to controls. No significant effects of CHQ on glutathione reductase, GSH, and MDA levels were seen in the liver. Fewer effects of CHQ were observed in the kidney where a decrease in GPX activity and an increase in MDA levels was seen. Lowering of antioxidant enzymes activities in the liver by CHQ could render the organ more susceptible to subsequent oxidative stress; while increased MDA production after CHQ treatment in the kidney indicate that the organ is being subjected to oxidative stress. This could have implications for prolonged chloroquine intake. Copyright © 1996 Elsevier Science Inc.
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A number of drugs have been studied for their effect on the metabolism of the antimalarial drug primaquine by human liver microsomes (N = 4) in vitro. The only metabolite generated was identified as carboxyprimaquine by co-chromatography with the authentic standard. Ketoconazole, a known inhibitor of cytochrome P450 isozymes, caused marked inhibition of carboxyprimaquine formation with ic₅₀ and K_i values of 15 and 6.7 μM, respectively. This finding and the dependency of metabolite formation on NADPH indicates that cytochrome P450 isozyme(s) catalysed metabolite production. Of compounds actually or likely to be coadministered with primaquine to malaria patients, only mefloquine produced any inhibition (K_i = 52.5 μM). Quinine, artemether, artesunate, halofantrine and chloroquine did not significantly inhibit metabolite formation. It seems unlikely that the concurrent administration of mefloquine, or other antimalarials, with primaquine will lead to appreciably altered disposition.
Mefloquine metabolism by human liver microsomes. Effect of other antimalarial drugs
1992, Biochemical Pharmacology
A number of drugs have been studied for their effect on the metabolism of the antimalarial drug mefloquine by human liver microsomes (N = 6) in vitro. The only metabolite generated was identified as carboxymefloquine by co-chromatography with the authentic standard. Ketoconazole caused marked inhibition of carboxymefloquine formation with ic₅₀ and K_i values of 7.5 and 11.2 μM, respectively. The inhibition by ketoconazole, a known inhibitor of cytochrome P450 isozymes, and the dependency of metabolite formation on the presence of NADPH indicated that cytochrome P450 isozyme(s) catalysed metabolite production. Of compounds actually or likely to be coadministered with mefloquine to malaria patients only primaquine and quinine produced marked inhibition (ic₅₀, 17.5 and 122 μM; K_i, 8.6 and 28.5 μM, respectively). However, despite these in vitro data with primaquine, clinical studies have failed to show any significant effect of single dose primaquine on the pharmacokinetics of mefloquine. With quinine, because peak plasma concentrations are very close to the K_i value, there is likely to be inhibition of mefloquine metabolism in patients receiving both drugs. Sulfadoxine, artemether, artesunate and tetracycline did not significantly inhibit carboxymefloquine formation.

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In vitro effects of quinoline derivatives on cytochrome p-450 and aminopyrine n-demethylase activity in rat hepatic microsomes

Abstract

Biochem. Pharmac.

Biochem. Pharmac.

Biochem. Pharmac.

Biochem. Pharmac.

Lancet

Biochem. Pharmac.

Biochem. Pharmac.

Toxic. appl. Pharmac.

J. biol. Chem.

J. biol. Chem.

Toxic. appl. Pharmac.

Biochem. Pharmac.