The impact of CYP2C9 genetics and oral contraceptives on cytochrome P450 2C9 phenotype.

CYP2C9-dependent drug metabolism is subject to large interindividual variation. To some extent, this is explained by genetic polymorphism with expression of enzyme variants that differ in catalytic activity. The aim of this study was to characterize the variation in CYP2C9 phenotype in relation to genotype, with further analysis of the CYP2C9 gene in metabolic outliers. A study population of 126 healthy white subjects were recruited and genotyped for the variant alleles, CYP2C9*1-3. In CYP2C9 phenotyping with losartan, three subpopulations were distinguished that differed in the number of CYP2C9*3 alleles (0, 1, or 2). A three-fold higher metabolic ratio (MR; urinary losartan/carboxymetabolite) was found comparing CYP2C9*1/*3 (n = 20) to CYP2C9*1/*1 (n = 81), but there was considerable variation within each genotype. Subjects genotyped as CYP2C9*1/*1, but with an unexpectedly slow oxidation of losartan, were selected for DNA-sequencing analysis of the CYP2C9 gene. Interestingly, single nucleotide polymorphisms (SNPs) could not be identified either in the 5'-flanking region, the nine exons, or exon-intron boundaries. However, sequencing of the CYP2C9 gene was also carried out in patients genotyped as CYP2C9*1/*1 but with an exceptionally low steady-state clearance of S-warfarin. Here, five different SNPs were identified. In further analysis of the healthy volunteers, it became evident that women on oral contraceptives (OCs) had slower oxidation of losartan (MR of losartan: 1.7) than women without OCs (MR of losartan: 0.86). This novel finding was not explained by a different frequency of variant alleles. In summary, CYP2C9 genotype and oral contraceptives both contribute to a large interindividual variation in CYP2C9 activity.     

Superior fixation and less periprosthetic stress-shielding of tibial components with a finned stem versus an I-beam block stem: a randomized RSA and DXA study with minimum 5 years’ follow-up

Background and purpose — The stem on the tibial component of total knee arthroplasty provides mechanical resistance to lift-off, shear forces, and torque. We compared tibial components with finned stems (FS) and I-beam block stems (IS) to assess differences in implant migration.

Patients and methods — In a patient-blinded RCT, 54 patients/knees (15 men) with knee osteoarthritis at a mean age of 77 years (70–90) were randomly allocated to receive tibial components with either a FS (n = 27) or an IS (n = 27). Through 5 to 7 years’ follow-up, implant migration was measured with RSA, periprosthetic bone mineral density (BMD) was measured with DXA, and surgeons reported American Knee Society Score (AKSS).

Results — At minimum 5 years’ follow-up, maximum total point motion (MTPM) was higher (p = 0.04) for IS (1.48?mm, 95% CI 0.81–2.16) than for FS (0.85?mm, CI 0.38–1.32) tibial components. Likewise, total rotation (TR) was higher (p = 0.03) for IS (1.51?, CI 0.78–2.24) than for FS (0.81?, CI 0.36–1.27). Tibial components with IS externally rotated 0.50° (CI –0.06 to 1.06) while FS internally rotated 0.09° (CI –0.20 to 0.38) (p = 0.03). Periprosthetic bone stress-shielding was higher (p < 0.01) up to 2 years’ follow-up for IS compared with FS in the regions medial to the stem (–13% vs. –2%) and posterior to the stem (–13% vs. –2%). Below the stem bone loss was also higher (p = 0.01) for IS compared with FS (–6% vs. +1%) up to 1-year follow-up. Knee score improved similarly in both groups up to 5 years’ follow-up.

Interpretation — Periprosthetic bone stress-shielding medial and posterior to the stem until 2 years, and tibial component migration at 5 years, was less for a finned compared with an I-shaped block stem design.

Trial registration: ClinicalTrials.gov identifier: NCT00175136.