Amy S. Etheridge

PHARMACOKINETICS AND DISPOSITION OF THE KAVALACTONE KAWAIN: INTERACTION WITH KAVA EXTRACT AND KAVALACTONES IN VIVO AND IN VITRO

Reported adverse drug interactions with the popular herb kava have spurred investigation of the mechanisms by which kava could mediate these effects. In vivo and in vitro experiments were conducted to examine the effects of kava extract and individual kavalactones on cytochrome P450 (P450) and P-glycoprotein activity. The oral pharmacokinetics of the kavalactone, kawain (100 mg/kg), were determined in rats with and without coadministration of kava extract (256 mg/kg) to study the effect of the extract on drug disposition. Kawain was well absorbed, with >90% of the dose eliminated within 72 h, chiefly in urine. Compared with kawain alone, coadministration with kava extract caused a tripling of kawain AUC0–8 h and a doubling of Cmax. However, a 7-day pretreatment with kava extract (256 mg /kg/day) had no effect on the pharmacokinetics of kawain administered on day 8. The 7-day pretreatment with kava extract only modestly induced hepatic P450 activities. The human hepatic microsomal P450s most strongly inhibited by kava extract (CYP2C9, CYP2C19, CYP2D6, CYP3A4) were inhibited to the same degree by a “composite” kava formulation composed of the six major kavalactones contained in the extract. Ki values for the inhibition of CYP2C9 and CYP2C19 activities by methysticin, dihydromethysticin, and desmethoxyyangonin ranged from 5 to 10 μM. Kava extract and kavalactones (≤9 μM) modestly stimulated P-glycoprotein ATPase activities. Taken together, the data indicate that kava can cause adverse drug reactions via inhibition of drug metabolism.

Metabolism and disposition of [14C]n-butyl-p-hydroxybenzoate in male and female Harlan Sprague Dawley rats following oral administration and dermal application

n-Butyl-p-hydroxybenzoate (n-butylparaben, BPB) is an antioxidant used in foods, pharmaceuticals and cosmetics. This study investigated the disposition of ring-labelled [14C]BPB in Harlan Sprague Dawley rats, and in rat and human hepatocytes. BPB was rapidly cleared in hepatocytes from rat (t1/2 = 3–4 min) and human (t1/2 = 20–30 min). The major metabolites detected in rat hepatocytes were hydroxybenzoic acid and in human hepatocytes were hydroxybenzoic acid and hydroxyhippuric acid. [14C]BPB was administered to male rats orally at 10, 100 or 1000 mg/kg, intravenously at 10 mg/kg and dermally at 10 and 100 mg/kg; female rats were administered oral doses at 10 mg/kg. Oral doses of BPB were well-absorbed (>83%) and eliminated chiefly in urine (83–84%); ≤1% of the radioactivity remained in tissues at 24 h or 72 h after dosing. About 4% and 8%, respectively, of 100 mg/kg dermal doses were absorbed in 24 h and 72 h, and about 50% of a 10 mg/kg dose was absorbed in 72 h. Metabolites detected in urine included those previously reported, BPB-glucuronide, BPB-sulfate, hydroxybenzoic acid and hydroxyhippuric acid, but also novel metabolites arising from ring hydroxylation followed by glucuronidation and sulfation.

Inhibition of Paclitaxel Metabolism In Vitro in Human Hepatocytes by Ginkgo biloba Preparations

Since the late 1980s, chemotherapy-induced cognitive impairment, also known as “chemobrain”, has been a recognized side effect in patients undergoing cancer treatment (). Although products containing Ginkgo biloba may be used by patients undergoing chemotherapy with paclitaxel and other agents, the potential for an herb–drug interaction with this combination has not been adequately explored. This report describes the inhibition of paclitaxel metabolism by Ginkgo preparations in vitro in human hepatocytes. Hydrolyzate of Ginkgo extract (10–100 mM in terpene lactone concentration) caused a dose-dependent inhibition of the 6α -hydroxylation of paclitaxel, the enzymatic activity responsible for the majority of the clearance of that drug in clinical applications; parent extract had no effect. Contrary to the assumed therapeutic benefit of Ginkgo, its concomitant use with paclitaxel could result in elevated blood levels of the chemotherapeutic, with attendant exacerbation of cognitive impairment and other toxic effects associated with cancer therapy.

Metabolism and disposition of 2-methoxy-4-nitroaniline in male and female Harlan Sprague Dawley rats and B6C3F1/N mice

The disposition of 2-Methoxy-4-nitroaniline (MNA) was investigated in male and female Harlan Sprague Dawley rats and B6C3F1/N mice following oral, intravenous, and dermal exposure to [14C]MNA at 2, 15, or 150 mg/kg. Clearance of MNA was investigated in male and female rat, mouse, and human hepatocytes. MNA was cleared slowly in hepatocytes from rat (t1/2 = 152–424 min) and human (t1/2 = 118–403 min) but faster in mouse (t1/2= 70–106 min). MNA was well-absorbed in rats and mice following oral administration and eliminated chiefly in urine (rats, 75–79%; mice, 55–68%) 72 h post dosing. Less than 1% of the radioactivity remained in tissues at 72 h. MNA was poorly absorbed following dermal application in rats (5.5%) and mice (10%) over 24 h. The major pathway of metabolism of MNA was via hydroxylation of the phenyl ring to form 6-hydroxy MNA; major metabolites detected were sulfate and glucuronide conjugates of 6-hydroxy MNA. Following oral administration, the percent of total radioactivity bound in tissues bound was highest in liver (43%) and red blood cells (30%), whereas the radioactivity bound to DNA was highest in cecum (160 pmol/mg DNA).