Glucuronidation converts clopidogrel to a strong time-dependent inhibitor of CYP2C8: a phase II metabolite as a perpetrator of drug-drug interactions.

Cerivastatin and repaglinide are substrates of cytochrome P450 (CYP)2C8, CYP3A4, and organic anion-transporting polypeptide (OATP)1B1. A recent study revealed an increased risk of rhabdomyolysis in patients using cerivastatin with clopidogrel, warranting further studies on clopidogrel interactions. In healthy volunteers, repaglinide area under the concentration-time curve (AUC(0-∞)) was increased 5.1-fold by a 300-mg loading dose of clopidogrel and 3.9-fold by continued administration of 75 mg clopidogrel daily. In vitro, we identified clopidogrel acyl-ß-D-glucuronide as a potent time-dependent inhibitor of CYP2C8. A physiologically based pharmacokinetic model indicated that inactivation of CYP2C8 by clopidogrel acyl-ß-D-glucuronide leads to uninterrupted 60-85% inhibition of CYP2C8 during daily clopidogrel treatment. Computational modeling resulted in docking of clopidogrel acyl-ß-D-glucuronide at the CYP2C8 active site with its thiophene moiety close to heme. The results indicate that clopidogrel is a strong CYP2C8 inhibitor via its acyl-ß-D-glucuronide and imply that glucuronide metabolites should be considered potential inhibitors of CYP enzymes.

Femoral neck bone mineral density after resurfacing hip arthroplasty.

INTRODUCTION: Resurfacing hip arthroplasty (RHA) has been suggested to provide an alternative to conventional total hip arthroplasty in younger, active patients. It seems to have an ability to conserve the bone mass on the femoral side. Some controversy exists regarding to the possible disadvantages of RHA and some of them are connected to poor femoral bone quality after surgery. Hence we wanted to study the bone mineral density changes 3 and 12 months after RHA. MATERIALS AND METHODS: A total of 26 patients (22 men and 4 women, 28 hips) underwent a hip resurfacing arthroplasty. The mean age of the patients was 55,2 (range 38-69) years. Bone mineral density (BMD) of the proximal femur was measured by using the dual-energy X-ray absorptiometry (DXA) postoperatively and within 3 and 12 months from surgery. For analysis, we divided the femoral neck area into four equal-sized regions of interest ranging from the prosthesis to the trochanter level. RESULTS: At three months follow-up the BMD changes varied between -5.1% (ROI C) and + 1.9% (ROI A), as compared with the immediate postoperative values. After one year follow-up the BMD changes were + 1.1% in the ROI A, + 5.4% in the ROI B, -3.9% in the ROI C and + 1.3% in the ROI D. The changes in BMD were not statistically significant. DISCUSSION: While there is still much debate and room for additional research in this topic, the results suggest that BMD is conserved in the femoral neck one year after hip resurfacing arthroplasty.

Grapefruit juice greatly reduces the plasma concentrations of the OATP2B1 and CYP3A4 substrate aliskiren.

In a randomized crossover study, 11 healthy volunteers ingested 200 ml of grapefruit juice or water three times a day for 5 days. On day 3, they ingested a single 150-mg dose of aliskiren. Grapefruit juice reduced aliskiren peak plasma concentration (C(max)) by 81% (range, 42-91%, P < 0.001), area under the plasma aliskiren concentration-time curve (AUC)(0-infinity) by 61% (range, 15-72%, P < 0.001), and elimination half-life (t(1/2)) from 26.1 to 23.6 h (P = 0.020). Therefore, concomitant use of aliskiren and grapefruit juice is best avoided.

Alendronate reduces periprosthetic bone loss after uncemented primary total hip arthroplasty - a 5-year follow-up of 16 patients.

BACKGROUND AND AIMS: Periprosthetic bone loss, especially in the proximal part of the femur, is common after cemented and uncemented total hip arthroplasty (THA). Short-term studies suggest that bisphosponates can minimize this bone loss related to stress-shielding phenomenon. The aim of the present randomized study was to investigate whether the positive effect of a 6 months alendronate treatment postoperatively still exists at five-year follow up. MATERIALS AND METHODS: Sixteen uncemented primary THA patients were randomized to receive either 10mg alendronate + 500 mg calcium (n = 7) or 500 mg calcium only (n = 9) daily for 6 months postoperatively. Periprosthetic bone mineral density (BMD) was measured with the dual X-ray absorptiometry (DXA) postoperatively and at 6, 12, 24, 36 and 60 months follow-up. RESULTS: At the 5-year follow up, the calcium group showed mean BMD decreases of 23.1% (SD 14.6) in the proximal part of the femur (prROI) and 9.6% (SD 14.9) in total femoral regions of interest (totROI). In the alendronate group the corresponding BMD decreases were 13.6% (SD 19.0) and 3.9% (SD 7.6) respectively. The positive effect of alendronate was already demonstrated during the first six months postoperatively. Subsequently the bone loss was equal in both groups, and the 5-year BMD changes were not significantly different between the groups. CONCLUSIONS: Alendronate seems to decrease early periprosthetic bone loss after arthroplasty but this pilot study could not provide enough evidence that the positive effect noted in the early postoperative period is still maintained 5 years after the operation.