Associations of the CYP3A5*3 and CYP3A4*1G polymorphisms with the pharmacokinetics of oral midazolam and the urinary 6ß-hydroxycortisol/cortisol ratio as markers of CYP3A activity in healthy male Chinese.

WHAT IS KNOWN AND OBJECTIVE: The oral plasma clearance of midazolam and the ratio of 6ß-hydroxycortisol (6ß-OHF) to cortisol (F) in urine are two potential markers for evaluating CYP3A activity in vivo. We assessed the influence of two common CYP3A polymorphisms on the pharmacokinetics of oral midazolam and urinary ratio of 6ß-OHF/F in healthy Chinese. METHODS: Single oral 15 mg doses of midazolam were given to 20 healthy male Chinese subjects who were genotyped for the CYP3A5*3 and CYP3A4*1G polymorphisms. The plasma concentrations of midazolam were determined by LC/MS/MS. Morning urine samples were collected after overnight fasting, and urine F and 6ß-OHF concentrations were measured using UPLC. RESULTS AND DISCUSSION: There were no significant correlations between the pharmacokinetic parameters of midazolam and urinary ratios of 6ß-OHF/F. The CYP3A polymorphisms examined had no significant associations with the urinary ratios of 6ß-OHF/F or the pharmacokinetics of midazolam. However, diplotype analysis suggested that CYP3A5 expressers with the CYP3A4*1/*1G genotype (n = 3) had significantly lower midazolam AUC0-∞ values (210·0 ± 33·5 vs. 313·9 ± 204·6 h∙ng/mL, P = 0·044) and higher CL/F values (1·16 ± 0·16 vs. 0·88 ± 0·48 L/h/kg, P = 0·005) compared to subjects with the CYP3A4*1/*1 genotype (n = 4), which is consistent with some previous studies with tacrolimus. WHAT IS NEW AND CONCLUSION: There were no significant associations between midazolam pharmacokinetic parameters and urinary ratios of 6ß-OHF/F and the two CYP3A polymorphisms were not associated with the urinary ratios of 6ß-OHF/F or midazolam pharmacokinetic parameters. The possible association of CYP3A5*3 and CYP3A4*1G polymorphisms on CYP3A activity and their potential interaction require confirmation in a larger study.

Affordable measurement of human total energy expenditure and body composition using one-tenth dose doubly labelled water.

BACKGROUND: The doubly labelled water (DLW) method is the technique of choice for measurement of free-living total energy expenditure (TEE) in humans. A major constraint on the clinical applicability of the method has been the expense of the (18)O isotope. METHOD: We have used a reduced-dose (one-tenth of the currently recommended standard dose) of DLW for the measurement of TEE and body composition in nine healthy adult male volunteers. RESULTS: TEE measured by reduced-dose DLW was positively correlated with resting energy expenditure measured by metabolic cart (r=0.87, P<0.01). Isotope-derived fat mass and body mass index were strongly correlated (r=0.86, P<0.01). In four subjects in whom we performed a complementary evaluation using standard-dose isotope enrichment, the TEE measurements were satisfactorily comparable (mean+/-s.d.: reduced dose 2586+/-155 kcal/day vs standard dose 2843+/-321 kcal/day; mean difference 257+/-265 kcal/day). CONCLUSION: These data indicate that DLW measurements of human energy expenditure and body composition can be performed at a substantially reduced dose (and cost) of isotope enrichment than is currently employed.

An investigation to show the effect of lung fluid on impedance cardiac output in the anaesthetized dog.

BACKGROUND: Accumulation of lung fluid in the critically ill patient is believed to attenuate impedance cardiac output (CO(IC)) measurements. However, this phenomenon has never been shown experimentally. METHODS: In eight anaesthetized and ventilated dogs (weight 15-22 kg) a high-precision flow probe was placed on the ascending aorta via a left thoracotomy incision and the direct cardiac output (CO(FP)) was measured. Simultaneous CO(IC) measurements were made using a RheoCardioMonitor (ACMA, Singapore). Lung oedema was induced by intravenous oleic acid 0.1 mg kg(-1). Lung fluid was assessed by the decrease in basal thoracic impedance (Z(b)). Percentage errors between the two methods (CO(IC)-CO(FP)) were calculated and compared as Z(b) decreased at 1 Omega intervals. RESULTS: During the experiment mean Z(b) decreased from 35.9 (sd 5.2) to 27.8 (6.5) Omega (P=0.0037). This occurred over a period of 225 (range 112-338) min and Z(b) decreased by 1 Omega every 51 (22-68) min. The presence of excessive lung fluid was confirmed at post-mortem. Before lung oedema was induced, CO(IC) was 1.5 (0.6) litre min(-1) and the corresponding value of CO(FP) was 1.5 (0.7) litre min(-1) (data from eight dogs). As Z(b) decreased, and lung fluid accumulated, the error between CO(IC) and CO(FP) widened (P<0.0001, anova for repeated measures). Eventually, CO(IC) decreased to 0.7 (0.3) litre min(-1) and the corresponding value of CO(FP) was 1.2 (0.3) litre min(-1) (DeltaZ(b)=5 Omega, data from six dogs). Mean arterial pressure, central venous pressure and systemic vascular resistance were kept constant. CONCLUSION: The presence of lung fluid attenuates CO(IC) measurements with respect to CO(FP).