Effects of cytochrome P450 inducers and inhibitors on the pharmacokinetics of intravenous furosemide in rats: involvement of CYP2C11, 2E1, 3A1 and 3A2 in furosemide metabolism.

OBJECTIVES: It has been reported that the non-renal clearance of furosemide was significantly faster in rats pretreated with phenobarbital but was not altered in rats pretreated with 3-methylcholanthrene. However, no studies on other cytochrome P450 (CYP) isozymes have yet been reported in rats. METHOD: Furosemide 20 mg/kg was administered intravenously to rats pretreated with various CYP inducers--3-methylcholanthrene, orphenadrine citrate and isoniazid, inducers of CYP1A1/2, 2B1/2 and 2E1, respectively, in rats--and inhibitors--SKF-525A (a non-specific inhibitor of CYP isozymes), sulfaphenazole, cimetidine, quinine hydrochloride and troleandomycin, inhibitors of CYP2C6, 2C11, 2D and 3A1/2, respectively, in rats. KEY FINDINGS: The non-renal clearance of furosemide was significantly faster (55.9% increase) in rats pretreated with isoniazid, but slower in those pretreated with cimetidine or troleandomycin (38.5% and 22.7% decreases, respectively), than controls. After incubation of furosemide with baculovirus-infected insect cells expressing CYP2C11, 2E1, 3A1 or 3A2, furosemide was metabolized via CYP2C11, 2E1, 3A1 and 3A2. CONCLUSIONS: These findings could help explain possible pharmacokinetic changes of furosemide in various rat disease models (where CYP2C11, 2E1, 3A1 and/or CYP3A2 are altered) and drug-drug interactions between furosemide and other drugs (mainly metabolized via CYP2C11, 2E1, 3A1 and/or 3A2).

Pharmacokinetics of baicalin in rats and its interactions with cyclosporin A, quinidine and SKF-525A: a microdialysis study.

Baicalin, a flavone glucuronide derived mainly from the root of Scutellaria baicalensis, has been used in traditional Chinese medicine as an anti-inflammatory and anti-viral agent. To explore whether the disposition of baicalin is related to multidrug resistance P-glycoprotein (P-gp), baicalin (3, 10 and 30 mg kg(-1); i. v.) was injected to rats for a pharmacokinetic study using microdialysis coupled with HPLC. The results indicate that baicalin goes through hepatobiliary excretion against a concentration gradient based on the blood-to-bile distribution ratio (AUCbile/AUCblood), but that AUCblood or AUCbile did not show any dose-related increase in the range from 3 to 30 mg kg(-1). Coadministration of cyclosporin A (CsA) or quinidine (both are P-gp inhibitors) was used to delineate the role of P-gp on baicalin disposition, while SKF-525A (a cytochrome P450 inhibitor) could specifically inhibit the cytochrome P450 catalysis of baicalin without crossing with P-gp function. Both CsA and quinidine promoted the active transport of baicalin into bile and reduced its level in blood, and this result was the same as that obtained by treating with SKF-525A. Hence, the association of the involvement of P-gp in active baicalin efflux into bile seems to be excluded since CsA and quinidine are also cytochrome P450 inhibitors. In addition, baicalin was not detected in the brain striatum after treating with baicalin alone in the present study. Also, neither CsA nor quinidine co-administered with baicalin is able to induce measurable levels of baicalin in rat brain, which suggests that baicalin might not be able to pass through the blood-brain barrier (BBB).

Hepatobiliary excretion of berberine.

Berberine is a bioactive herbal ingredient isolated from the roots and bark of Berberis aristata or Coptis chinensis. To investigate the detailed pharmacokinetics of berberine and its mechanisms of hepatobiliary excretion, an in vivo microdialysis coupled with high-performance liquid chromatography was performed. In the control group, rats received berberine alone; in the drug-treated group, 10 min before berberine administration, the rats were injected with cyclosporin A (CsA), a P-glycoprotein (P-gp) inhibitor; quinidine, both organic cation transport (OCT) and P-gp inhibitors; SKF-525A (proadifen), a cytochrome P450 inhibitor; and probenecid to inhibit the glucuronidation. The results indicate that berberine displays a linear pharmacokinetic phenomenon in the dosage range from 10 to 20 mg kg(-1), since a proportional increase in the area under the concentration-time curve (AUC) of berberine was observed in this dosage range. Moreover, berberine was processed through hepatobiliary excretion against a concentration gradient based on the bile-to-blood distribution ratio (AUC(bile)/AUC(blood)); the active berberine efflux might be affected by P-gp and OCT since coadministration of berberine and CsA or quinidine at the same dosage of 10 mg kg(-1) significantly decreased the berberine amount in bile. In addition, berberine was metabolized in the liver with phase I demethylation and phase II glucuronidation, as identified by liquid chromatography/tandem mass spectrometry. Also, the phase I metabolism of berberine was partially reduced by SKF-525A treatment, but the phase II glucuronidation of berberine was not obviously affected by probenecid under the present study design.