Marginal increase of sunitinib exposure by grapefruit juice

Clinical Oncolog

Effect of oral contraceptives on the transport of chlorpromazine across the CACO-2 intestinal epithelial cell line

Abstract In previous chlorpromazine pharmacokinetic studies a dramatic elevation in blood plasma levels of this drug was observed when taken in combination with oral contraceptives. Different mechanisms have been postulated to explain this observation. The aim of the study was to investigate whether oral contraceptives such as ethinyloestradiol and progesterone enhance the absorption of chlorpromazine by means of inhibiting P-glycoprotein (P-gp) and if this effect is mainly due to ethinyloestradiol or progesterone or their combination. The Caco-2 cell line was used as an in vitro model to study the effects of these compounds on the transport of chlorpromazine. Both apical to basolateral (AP-BL) and basolateral to apical (BL-AP) transport studies were done on chlorpromazine in combination with different compounds. Ethinyloestradiol enhanced the AP-BL cumulative transport of chlorpromazine by 11.5% compared to the control group, which was also statistically significantly higher than the effect caused by progesterone (0.8%). A combination of these two steroidal hormones enhanced the cumulative transport of chlorpromazine by only 2.0% compared to the control group. This indicates the possible existence of separate drugbinding sites for these two hormones and chlorpromazine on P-gp. The drug-binding site (or receptor) for progesterone probably interacts allosterically with the binding site for ethinyloestradiol and thereby decreasing its transport enhancing effects on chlorpromazine

The effect of bexarotene on atorvastatin pharmacokinetics: results from a phase I trial of bexarotene plus chemotherapy in patients with advanced non-small cell lung cancer

Purpose Bexarotene (Targretin® capsules) is a retinoid-X-receptor agonist and an inducer of CYP3A4-mediated metabolism. This phase I trial evaluated the pharmacokinetic (PK) and drug–drug interactions of bexarotene with chemotherapy and a lipid-lowering agent (atorvastatin or fenofibrate). This trial was run in parallel with phase III trials of the combinations to determine whether repeated doses of bexarotene capsules affect the pharmacokinetics (PK) of the chemotherapeutic or the lipid-lowering agents. Methods Patients (n = 48) with advanced non-small cell lung cancer were treated with repetitive cycles of either paclitaxel/carboplatin or cisplatin/vinorelbine chemotherapy, bexarotene (400 mg/m2/day) administered continuously starting on day 4 of chemotherapy, and a lipid-lowering drug, either atorvastatin or fenofibrate, starting at least 5 days before chemotherapy due to hypertriglyceridemia induced by bexarotene. Extensive plasma sampling to characterize the PK profiles of the lipid-lowering drugs, relevant chemotherapy agents was performed on day 1 (without bexarotene) and during chemotherapy cycles 2 or 3 (with bexarotene). Results Here, we report the drug–drug interactions between the lipid-lowering agents and bexarotene. Mean atorvastatin clearance and dose-corrected AUC values were reduced by nearly 50% with the addition of concomitant bexarotene. As fenofibrate was less effective at controlling hypertriglyceridemia, too few patients received this agent to make any meaningful conclusions about drug–drug interactions. Conclusions A drug–drug interaction was seen in this trial with bexarotene co-administration leading to a significant reduction in the AUC of atorvastatin. The likely mechanism for this interaction is through induction of CYP3A4 by bexarotene given the role of this enzyme in the metabolism of atorvastatin. Knowledge of this interaction is important for optimizing lipid management with atorvastatin for patients receiving bexarotene