Interactions of imidazole antifungal agents with purified cytochrome P-450 proteins

doi:10.1016/0006-2952(87)90670-8

Biochemical Pharmacology

Volume 36, Issue 24, 15 December 1987, Pages 4277-4281

https://doi.org/10.1016/0006-2952(87)90670-8 Get rights and content

Abstract

The imidazole N-substituted antifungal agents ketoconazole, miconazole and clotrimazole have been shown to be potent inhibitors of oxidative metabolism by both a phenobarbital-induced cytochrome P-450 (P-450_b) and a 3-methylcholanthrene-induced cytochrome P-448-protein (P-450_c) in reconstituted systems. All three compounds inhibited the cytochrome P-450_b-dependent 7-pentoxyresorufin-O-dealkylase and the cytochrome P-450_c-dependent 7-ethoxyresorufin-O-deethylase activities. When 7-benzyloxyresorufin and 7-ethoxycoumarin were employed as substrates with both cytochrome preparations, all three antifungal compounds exhibited selective inhibition of the cytochrome P-450_b preparation; ketoconazole was always the weakest inhibitor. The three antifungal agents were also shown to elicit a type II difference spectral interaction with both isoenzymes, the magnitude of the spectral interaction being greater with the cytochrome P-450_b preparation.

References (43)

M.J. Henry et al.
Pestic. Biochem. Physiol.
(1984)
D.W. Nebert et al.
TIPS
(1985)
D.F.V. Lewis et al.
Biochem. Pharmac.
(1986)
F.P. Guengerich et al.
Archs Biochem. Biophys.
(1980)
Y. Yasukochi et al.
J. biol. Chem.
(1976)
K.-C. Cheng et al.
J. biol. Chem.
(1982)
J.S. French et al.
Archs Biochem. Biophys.
(1979)
D.A. Haugen et al.
J. biol. Chem.
(1975)
O.H. Lowry et al.
J. biol. Chem.
(1951)
G.L. Peterson
Analyt. Biochem.
(1977)

C. Fenner et al.

Analyt. Biochem.

(1975)

G.G. Gibson et al.

J. biol. Chem.

(1978)

M.D. Burke et al.

Biochem. Pharmac.

(1985)

C. Razzouk et al.

Biochem. biophys. Res. Commun.

(1978)

J.J. Sheets et al.

Biochem. Pharmac.

(1986)

T.D. Rogerson et al.

Biochem. Pharmac.

(1977)

R.A. Swanson et al.

J. biol. Chem.

(1979)

H. Vanden-Bossche et al.

Pest. Sci.

(1984)

C. Suresh et al.

Endocrinology

(1985)

J.I. Mason et al.

Biochem. Pharmac.

(1985)

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The presence of cytochrome b5 (equimolar) had only a small effect on the amplitude of the reaction of ketoconazole (2 μM final concentration) with P450 3A4 (2 μM) (Fig. 7A). With equal amounts of P450 3A4 and ketoconazole, the reaction X + Y → Z (where X is P450 3A4, Y is ketoconazole, and Z is the complex) is mathematically equivalent to 2X → Z, and a plot of 1/[unbound P450] versus time (Fig. 7B) yields an apparent second-order rate constant as the slope (52). However, this value was low (5.4 × 105 M−1 s−1) and is deficient in that the system is more complex than a simple two-state reaction (see later).
Cytochrome P450 (P450) 3A4 is the enzyme most involved in the metabolism of drugs and can also oxidize numerous steroids. This enzyme is also involved in one-half of pharmacokinetic drug–drug interactions, but details of the exact mechanisms of P450 3A4 inhibition are still unclear in many cases. Ketoconazole, clotrimazole, ritonavir, indinavir, and itraconazole are strong inhibitors; analysis of the kinetics of reversal of inhibition with the model substrate 7-benzoyl quinoline showed lag phases in several cases, consistent with multiple structures of P450 3A4 inhibitor complexes. Lags in the onset of inhibition were observed when inhibitors were added to P450 3A4 in 7-benzoyl quinoline O-debenzylation reactions, and similar patterns were observed for inhibition of testosterone 6β-hydroxylation by ritonavir and indinavir. Upon mixing with inhibitors, P450 3A4 showed rapid binding as judged by a spectral shift with at least partial high-spin iron character, followed by a slower conversion to a low-spin iron–nitrogen complex. The changes were best described by two intermediate complexes, one being a partial high-spin form and the second another intermediate, with half-lives of seconds. The kinetics could be modeled in a system involving initial loose binding of inhibitor, followed by a slow step leading to a tighter complex on a multisecond time scale. Although some more complex possibilities cannot be dismissed, these results describe a system in which conformationally distinct forms of P450 3A4 bind inhibitors rapidly and two distinct P450–inhibitor complexes exist en route to the final enzyme–inhibitor complex with full inhibitory activity.
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Owing to the risk of KTZ‐induced hepatotoxicity and serious drug–drug interactions, the current use of KTZ as an antifungal agent tends to be restricted to more serious infections that are resistant to other safer azoles.5,6 However, KTZ is still a widely used prototypical CYP3A inhibitor and P‐glycoprotein (Pgp) modulator for in vitro and in vivo drug interaction studies.7–11 Stereoselectivity in KTZ pharmacodynamics is present with (−)‐KTZ being the more potent antifungal and CYP3A inhibitory enantiomer.12
Hyperlipidemia (HL) was previously shown to lower liver uptake of the more potent (−) enantiomer of ketoconazole (KTZ) in rat. The current study examined the possible modifying influence of experimental HL on a KTZ pharmacokinetic interaction with midazolam (MDZ). Normolipidemic and hyperlipidemic rats were administered a single intravenous dose of MDZ (5 mg/kg) with or without a single oral dose of racemic KTZ (40 mg/kg). Serial blood samples were collected over 8 h following MDZ injections via jugular vein cannulas. Plasma was jointly assayed for MDZ and KTZ concentrations using a validated assay. MDZ mean clearance (CL) was unchanged by KTZ coadministration. HL caused a significantly 61% lower MDZ‐unbound fraction and decreases in volume of distribution (VD) but by itself had no effect on MDZ CL. This suggested that MDZ could bind to lipoproteins. With KTZ coadministered to hyperlipidemic rats, there were significant decreases in MDZ CL and VD. HL caused a decrease in unbound plasma fraction of oral KTZ but no significant difference in its pharmacokinetics. HL caused a more pronounced KTZ ‐associated inhibition of MDZ CL. This may be related to the decrease of MDZ's unbound fraction and perhaps to attenuation of CYP3A by HL in the rat. © 2011 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 100:4986–4992, 2011
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Arachidonic acid (AA) can undergo monooxygenation or epoxidation by enzymes in the cytochrome P450 (CYP) family in the brain, kidney, lung, vasculature, and the liver. CYP-AA metabolites, 19- and 20-hydroxyeicosatetraenoic acids (HETEs), epoxyeicosatrienoic acids (EETs) and diHETEs have different biological properties based on sites of production and can be stored in tissue lipids and released in response to hormonal stimuli. 20-HETE is a vasoconstrictor, causing blockade of Ca⁺⁺-activated K⁺ (K_Ca) channels. Inhibition of the formation of nitric oxide (NO) by 20-HETE mediates most of the cGMP-independent component of the vasodilator response to NO. 20-HETE elicits a potent dilator response in human and rabbit pulmonary vascular and bronchiole rings that is dependent on an intact endothelium and COX. 20-HETE is also a vascular oxygen sensor, inhibits Na⁺/K⁺-ATPase activity, is an endogenous inhibitor of the Na⁺–K⁺–2Cl⁻cotransporter, mediates the mitogenic actions of vasoactive agents and growth factors in many tissues and plays a significant role in angiogenesis. EETs, produced by the vascular endothelium, are potent dilators. EETs hyperpolarize VSM cells by activating K_Ca channels. Several investigators have proposed that one or more EETs may serve as endothelial-derived hyperpolarizing factors (EDHF). EETs constrict human and rabbit bronchioles, are potent mediators of insulin and glucagon release in isolated rat pancreatic islets, and have anti-inflammatory activity.
Compared with other organs, the liver has the highest total CYP content and contains the highest levels of individual CYP enzymes involved in the metabolism of fatty acids. In humans, 50–75% of CYP-dependent AA metabolites formed by liver microsomes are ω/ω-OH-AA, mainly w-OH-AA, i.e. 20HETE, and 13–28% are EETs. Very little information is available on the role of 19- and 20-HETE and EETs in liver function. EETs are involved in vasopressin-induced glycogenolysis, probably via the activation of phosphorylase. In the portal vein, inhibition of EETs exerts profound effects on a variety of K-channel activities in smooth muscles of this vessel. 20-HETE is a weak, COX-dependent, vasoconstrictor of the portal circulation. EETs, particularly 11,12-EET, cause vasoconstriction of the porto-sinusoidal circulation. Increased synthesis of EETs in portal vessels and/or sinusoids or increased levels in blood from the meseneric circulation may participate in the pathophysiology of portal hypertension of cirrhosis. CYP-dependent AA metabolites are involved in the pathophysiology of portal hypertension, not only by increasing resistance in the porto-sinusoidal circulation, but also by increasing portal inflow through mesenteric vasodilatation. In patients with cirrhosis, urinary 20-HETE is several-fold higher than PGs and TxB2, whereas in normal subjects, 20-HETE and PGs are excreted at similar rates. Thus, 20-HETE is probably produced in increased amounts in the preglomerular microcirculation accounting for the functional decrease of flow and increase in sodium reabsorption.
In conclusion, CYP-AA metabolites represent a group of compounds that participate in the regulation of liver metabolic activity and hemodynamics. They appear to be deeply involved in abnormalities related to liver diseases, particularly cirrhosis, and play a key role in the pathophysiology of portal hypertension and renal failure.

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Interactions of imidazole antifungal agents with purified cytochrome P-450 proteins

Abstract

Pestic. Biochem. Physiol.

TIPS

Biochem. Pharmac.

Archs Biochem. Biophys.

J. biol. Chem.

J. biol. Chem.

Archs Biochem. Biophys.

J. biol. Chem.

J. biol. Chem.

Analyt. Biochem.

Analyt. Biochem.

J. biol. Chem.

Biochem. Pharmac.

Biochem. biophys. Res. Commun.

Biochem. Pharmac.

Biochem. Pharmac.

J. biol. Chem.

Pest. Sci.

Endocrinology

Biochem. Pharmac.