Pharmacokinetics of midazolam in CYP3A4- and CYP3A5-genotyped subjects

Objective: We investigated whether differences in pharmacokinetics of midazolam, a CYP3A probe, could be demonstrated between subjects with different CYP3A4 and CYP3A5 genotypes. Methods: Plasma concentrations of midazolam, and of total (conjugated + unconjugated) 1′OH-midazolam, and 4′OH-midazolam were measured after the oral administration of 7.5mg or of 75µg of midazolam in 21 healthy subjects. Results: CYP3A5*7, CYP3A4*1E, CYP3A4*2, CYP3A4*4, CYP3A4*5, CYP3A4*6, CYP3A4*8, CYP3A4*11, CYP3A4*12, CYP3A4*13, CYP3A4*17 and CYP3A4*18 alleles were not identified in the 21 subjects. CYP3A5*3, CYP3A5*6, CYP3A4*1B and CYP3A4*1F alleles were identified in 20, 1, 4 and 2 subjects, respectively. No statistically significant differences were observed for the AUCinf values between the different genotypes after the 75-µg or the 7.5-mg dose. Conclusion: Presently, CYP3A4 and CYP3A5 genotyping methods do not sufficiently reflect the inter-individual variability of CYP3A activit

Oral administration of a low dose of midazolam (75μg) as an in vivo probe for CYP3A activity

Objective: We investigated whether the oral administration of a low dose (75µg) of midazolam, a CYP3A probe, can be used to measure the in vivo CYP3A activity. Methods: Plasma concentrations of midazolam, 1′OH-midazolam and 4′OH-midazolam were measured after the oral administration of 7.5mg and 75µg midazolam in 13 healthy subjects without medication, in four subjects pretreated for 2days with ketoconazole (200mg b.i.d.), a CYP3A inhibitor, and in four subjects pretreated for 4days with rifampicin (450mg q.d.), a CYP3A inducer. Results: After oral administration of 75µg midazolam, the 30-min total (unconjugated + conjugated) 1′OH-midazolam/midazolam ratios measured in the groups without co-medication, with ketoconazole and with rifampicin were (mean±SD): 6.23±2.61, 0.79±0.39 and 56.1±12.4, respectively. No side effects were reported by the subjects taking this low dose of midazolam. Good correlations were observed between the 30-min total 1′OH-midazolam/midazolam ratio and midazolam clearance in the group without co-medication (r2=0.64, P<0.001) and in the three groups taken together (r2=0.91, P<0.0001). Good correlations were also observed between midazolam plasma levels and midazolam clearance, measured between 1.5h and 4h. Conclusion: A low oral dose of midazolam can be used to phenotype CYP3A, either by the determination of total 1′OH-midazolam/midazolam ratios at 30min or by the determination of midazolam plasma levels between 1.5h and 4h after its administratio

Lack of the mesodermal homeodomain protein MEOX1 disrupts sclerotome polarity and leads to a remodeling of the cranio-cervical joints of the axial skeleton

AbstractMeox1 and Meox2 are two related homeodomain transcription factor genes that together are essential for the development of all somite compartments. Here we show that mice homozygous for Meox1 mutations alone have abnormalities that are restricted to the sclerotome and its derivatives. A prominent and consistent phenotype of these mutations is a remodeling of the cranio-cervical joints whose major feature is the assimilation of the atlas into the basioccipital bone so that the skull rests on the axis. These abnormalities can be traced back to changes in the relative rates of cell proliferation in the rostral and caudal sclerotome compartments, and they are associated with alterations in the expression of at least three transcription factor genes, Tbx18, Uncx, and Bapx1. As previously observed for Bapx1, MEOX1 protein occupies evolutionarily conserved promoter regions of Tbx18 and Uncx, suggesting that Meox1 regulates these genes at least in part directly. Hence, Meox1 is part of a regulatory circuit that serves an essential, non-redundant function in the maintenance of rostro-caudal sclerotome polarity and axial skeleton formation