1 By performing microdialysis, this study investigated the pharmacokinetics of unbound camptothecin in rat blood, brain and bile in the presence of P-glycoprotein mediated transport modulators (cyclosporin A, berberine, quercetin, naringin and naringenin). Pharmacokinetic parameters of camptothecin were assessed using a non-compartmental model. 2 Camptothecin rapidly crosses the blood-brain barrier (BBB) within 20 min after camptothecin administration. The disposition of camptothecin in rat bile appeared to have a slow elimination phase and a peak concentration after 20 min of camptothecin administration. The area under the concentration versus time curve (AUC) for camptothecin in bile signi®cantly surpassed that in blood, suggesting active transport of hepatobiliary excretion. 3 In the presence of cyclosporin A camptothecin AUC, in the brain, was signi®cantly elevated but no signi®cant change in the presence of berberine, quercetin, naringin and naringenin. 4 With treatment by smaller doses of quercetin (0.1 mg kg 71 ), naringin (10 mg kg 71 ) and naringenin (10 mg kg 71 ), they signi®cantly diminished the camptothecin AUC in bile, but was not altered by the treatment of berberine (20 mg kg 71 ), a higher dose of quercetin (10 mg kg 71 ), and cyclosporin A treated (20 mg kg 71 ) and pretreated groups. 5 The distribution ratio (AUC bile /AUC blood ) of camptothecin in bile was decreased in the cyclosporin A, quercetin, naringin and naringenin treated groups. However, the distribution ratio in the brain was increased in the cyclosporin A groups, but was decreased in the groups treated with quercetin, naringin and naringenin. These results revealed that P-glycoprotein might modulate hepatobiliary excretion and BBB penetration of camptothecin.

This article reviews a number of specific pharmacological considerations for patients with prosthetic heart valves. All patients with mechanical heart valves should be anticoagulated. In the past, an International Normalised Ratio (INR) of 2.5 to 4.5 has been recommended. Recent nonrandomised studies have suggested that a patient with a prosthetic valve who is at low risk for thromboembolic events could have an INR ranging from 1.8 to 3.5. The lower end of this range should only be used for patients at higher than average risk of haemorrhage, until randomised data show that levels below 2.5 may be applied universally. In high-risk patients (particularly those with previous thromboembolic events) low dose aspirin should be added. During noncardiac surgery, a patient at low risk for thromboembolic events could be managed by discontinuing anticoagulation 3 days before the operation, with warfarin recommenced as soon as possible afterwards. Perioperative heparinisation would be appropriate in a higher risk patient. Women with prosthetic heart valves wishing to become pregnant should be converted to the use of twice-daily subcutaneous heparin injections. Patients with bioprosthetic valves can be managed without anticoagulation unless they have some other reason to require it. Patients at high risk should be treated with aspirin or warfarin. Thrombolytic therapy for acute valve thrombosis should be used for those who are haemodynamically compromised and therefore have a high risk of mortality from operative intervention. All patients with prosthetic heart valves undergoing invasive procedures potentially causing bacteraemia should receive antibiotic prophylaxis for endocarditis. The actual drugs used depend on the likely nature of the bacteraemia, and any possible patient hypersensitivity.