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Stephen D Hall

Publications and source records attributed to Stephen D Hall.

At least 19 recordsLinked to original sources
PubMed2006

Selective metabolism of vincristine in vitro by CYP3A5.

Clinical outcomes of vincristine therapy, both neurotoxicity and efficacy, are unpredictable, and the reported pharmacokinetics of vincristine have considerable interindividual variability. In vitro and in vivo data support a dominant role for CYP3A enzymes in the elimination of vincristine. Consequently, genetic polymorphisms in cytochrome P450 (P450) expression may contribute to the interindividual variability in clinical response, but the contributions of individual P450s and the primary pathways of vincristine metabolism have not been defined. In the present study, vincristine was incubated with a library of cDNA-expressed P450s, and the major oxidative metabolites were identified. CYP3A4 and CYP3A5 were the only P450s to support substantial loss of parent drug and formation of the previously unidentified, major metabolite (M1). The structure of M1, arising as a result of an oxidative cleavage of the piperidine ring of the dihydro-hydroxycatharanthine unit of vincristine, was conclusively established after conversion to suitable derivatives followed by spectroscopic analysis, and a new pathway for vincristine metabolism is proposed. CYP3A5 was more efficient in catalyzing the formation of M1 compared with CYP3A4 (9- to 14-fold higher intrinsic clearance for CYP3A5). The formation of M1 was stimulated (3-fold) by the presence of coexpressed cytochrome b5, but the relative efficiencies of M1 formation by CYP3A4 and CYP3A5 were unaffected. Our findings demonstrate that in contrast to most CYP3A biotransformations, the oxidation of vincristine is considerably more efficient with CYP3A5 than with CYP3A4. We conclude that common genetic polymorphisms in CYP3A5 expression may contribute to the interindividual variability in the systemic elimination of vincristine.

Animals↗
PubMed2006

Vincristine transcriptional regulation of efflux drug transporters in carcinoma cell lines.

The increased expression of drug transporters following cancer chemotherapy contributes to resistance. This may reflect transcriptional up-regulation and/or clonal selection. We quantified the expression of mRNA for ABCB1 (mdr1), ABCC1 (mrp1), ABCC2 (mrp2) and ABCC3 (mrp3) to evaluate the potential contribution of induction. ABCB1, ABCC1-3 mRNAs were quantified by real time RT-PCR and normalized to GAPDH. We used intestinal cells that express high pregnane X receptor (LS174T), low pregnane X receptor (Caco-2) and lung cells (A549) that express glucocorticoid receptor and low pregnane X receptor. Rifampin (10 microM) caused significant induction of ABCB1 (595+/-263%, p<0.05) in LS174T cells but induction was absent in Caco-2 or A549 cells. ABCC1 was not induced in any cell at 24, 48 and 72 h following rifampin treatment. In contrast, vincristine (10 nM and 100 nM), a ligand for ABCB1 and ABCC1-3 and a potential PXR/CAR ligand, induced ABCC2 and ABCC3 expression in LS174T cells at 48 h (372+/-87% and 303+/-42%, respectively, p<0.05). A similar induction of ABCC2 and ABCC3 genes was also seen with 10 nM VCR in A549 cells following 48 h treatment. In summary, there may be a significant contribution of transcriptional activation to multi-drug resistance. However, this is cell selective and is not necessarily dependent on PXR mediated effects.

Base Sequence↗
PubMed2006

Stochastic prediction of CYP3A-mediated inhibition of midazolam clearance by ketoconazole.

Conventional methods to forecast CYP3A-mediated drug-drug interactions have not employed stochastic approaches that integrate pharmacokinetic (PK) variability and relevant covariates to predict inhibition in terms of probability and uncertainty. Empirical approaches to predict the extent of inhibition may not account for nonlinear or non-steady-state conditions, such as first-pass effects or accumulation of inhibitor concentration with multiple dosing. A physiologically based PK model was developed to predict the inhibition of CYP3A by ketoconazole (KTZ), using midazolam (MDZ) as the substrate. The model integrated PK models of MDZ and KTZ, in vitro inhibition kinetics of KTZ, and the variability and uncertainty associated with these parameters. This model predicted the time- and dose-dependent inhibitory effect of KTZ on MDZ oral clearance. The predictive performance of the model was validated using the results of five published KTZ-MDZ studies. The model improves the accuracy of predicting the inhibitory effect of increasing KTZ dosing on MDZ PK by incorporating a saturable KTZ efflux from the site of enzyme inhibition in the liver. The results of simulations using the model supported the KTZ dose of 400 mg once daily as the optimal regimen to achieve maximum inhibition by KTZ. Sensitivity analyses revealed that the most influential variable on the prediction of inhibition was the fractional clearance of MDZ mediated by CYP3A. The model may be used prospectively to improve the quantitative prediction of CYP3A inhibition and aid the optimization of study designs for CYP3A-mediated drug-drug interaction studies in drug development.

Age Factors↗
PubMed2006

The effect of short- and long-term administration of verapamil on the disposition of cytochrome P450 3A and P-glycoprotein substrates.

BACKGROUND: Verapamil has the capability to inhibit and induce cytochrome P450 (CYP) 3A and P-glycoprotein (P-gp), but the relative extent and time course of these events in vivo are unclear. The effect of verapamil on CYP3A and P-gp activity was determined by examining its effect on its own disposition and on the disposition of fexofenadine, respectively. METHODS: Twelve healthy volunteers received 60 mg fexofenadine alone or after administration of 240 mg verapamil for 1, 10, and 38 days. The concentrations of verapamil and norverapamil, as well as their enantiomers, were quantified in serum by chiral HPLC. The concentrations of fexofenadine and its metabolite, azacyclonol, were quantified in serum and urine by liquid chromatography-mass spectrometry. RESULTS: The mean +/- SD maximum serum concentration (Cmax) and the area under the serum concentration-time curve of S-verapamil increased significantly on days 10 (40 +/- 21 ng/mL [P = .00044] and 433 +/- 316 ng.h.mL(-1) [P = .00047], respectively) and 38 (42 +/- 27 ng/mL [P = .019] and 433 +/- 256 ng.h.mL(-1) [P = .0081], respectively) compared with day 1 (21 +/- 12 ng/mL and 222 +/- 156 ng.h.mL(-1), respectively). The oral clearance (CLoral) of S-verapamil decreased significantly from 702 +/- 304 L/h on day 1 to 377 +/- 210 L/h on day 10 (P = .0029) and 449 +/- 419 L/h on day 38 (P = .05). Similar trends were observed for the Cmax and area under the serum concentration-time curve of R-verapamil and R- and S-norverapamil. All subjects showed a significant decrease in the CLoral of fexofenadine after a single dose (98 +/- 54 L/h, P = .00105) and 10-day dosing (102 +/- 40 L/h, P = .0011) of verapamil compared with the control value (156 +/- 69 L/h). The Cmax of fexofenadine was significantly increased by a single dose (165 +/- 42 ng/mL, P = .0005) and 10-day dosing (148 +/- 39 ng/mL, P = .0008) of verapamil compared with the control value (114 +/- 45 ng/mL). No significant difference in fexofenadine Cmax (P = .37) and CLoral (P = .43) was observed between the control values and values at 38 days of verapamil treatment. CONCLUSION: Verapamil inhibited CYP3A activity, with a maximum effect occurring within 10 days. Short-term administration of verapamil caused net inhibition of intestinal P-gp, whereas long-term administration of verapamil induced P-gp activity.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2006

Noninvasive positive-pressure ventilation: An experimental model to assess air and particle dispersion.

BACKGROUND: Health-care workers are concerned about the risk of acquiring contagious diseases such as severe acute respiratory syndrome and avian influenza after recent outbreaks. We studied exhaled air and particle dispersion through an oronasal mask attached to a human-patient simulator (HPS) during noninvasive positive-pressure ventilation (NPPV). METHODS: Airflow was marked with intrapulmonary smoke for visualization. Therapy with inspiratory positive airway pressure (IPAP) was started at 10 cm H2O and gradually increased to 18 cm H2O, whereas expiratory positive airway pressure was maintained at 4 cm H2O. A leakage jet plume was revealed by a laser light sheet and images captured by video. Smoke concentration in the plume was estimated from the light scattered by smoke particles. FINDINGS: A jet plume of air leaked through the mask exhaust holes to a radial distance of 0.25 m from the mask during the application of IPAP at 10 cm H2O with some leakage from the nasal bridge. The leakage plume exposure probability was highest about 60 to 80 mm lateral to the median sagittal plane of the HPS. Without nasal bridge leakage, the jet plume from the exhaust holes increased to a 0.40-m radius from the mask, whereas exposure probability was highest about 0.28 m above the patient. When IPAP was increased to 18 cm H2O, the vertical plume extended to 0.45 m above the patient with some horizontal spreading along the ward ceiling. CONCLUSION: Substantial exposure to exhaled air occurs within a 0.5-m radius of patients receiving NPPV. Medical wards should be designed with an architectural aerodynamics approach and knowledge of air/particle dispersion from common mechanical ventilatory techniques.

Air Movements↗
PubMed2006

Airflows around oxygen masks: A potential source of infection?

Patients with respiratory infections often require the use of supplemental oxygen via oxygen masks, which, in the hospital, may become sources of aerosolized infectious pathogens. To assess this risk, a human lung model (respiration rate, 12 breaths/min) was designed to test the potential for a simple oxygen mask at a common setting (4 L/min) to disperse potentially infectious exhaled air into the surrounding area. A laser sheet was used to illuminate the exhaled air from the mask, which contained fine tracer smoke particles. An analysis of captured digital images showed that the exhaled air at the peak of simulated exhalation reached a distance of approximately 0.40 m.

Aerosols↗
PubMed2005

The missing link: analogous human and primate cortical gamma oscillations.

Recent animal studies highlighting the relationship between functional imaging signals and the underlying neuronal activity have revealed the potential capabilities of non-invasive methods. However, the valuable exchange of information between animal and human studies remains restricted by the limited evidence of direct physiological links between species. In this study we used magnetoencephalography (MEG) to investigate the occurrence of 30-70 Hz (gamma) oscillations in human visual cortex, induced by the presentation of visual stimuli of varying contrast. These oscillations, well described in the animal literature, were observed in retinotopically concordant locations of visual cortex and show striking similarity to those found in primate visual cortex using surgically implanted electrodes. The amplitude of the gamma oscillations increases linearly with stimulus contrast in strong correlation with the gamma oscillations found in the local field potential (LFP) of the macaque. We demonstrate that non-invasive magnetic field measurements of gamma oscillations in human visual cortex concur with invasive measures of activation in primate visual cortex, suggesting both a direct representation of underlying neuronal activity and a concurrence between human and primate cortical activity.

Algorithms↗
PubMed2005

GLM-beamformer method demonstrates stationary field, alpha ERD and gamma ERS co-localisation with fMRI BOLD response in visual cortex.

Recently, we introduced a new 'GLM-beamformer' technique for MEG analysis that enables accurate localisation of both phase-locked and non-phase-locked neuromagnetic effects, and their representation as statistical parametric maps (SPMs). This provides a useful framework for comparison of the full range of MEG responses with fMRI BOLD results. This paper reports a 'proof of principle' study using a simple visual paradigm (static checkerboard). The five subjects each underwent both MEG and fMRI paradigms. We demonstrate, for the first time, the presence of a sustained (DC) field in the visual cortex, and its co-localisation with the visual BOLD response. The GLM-beamformer analysis method is also used to investigate the main non-phase-locked oscillatory effects: an event-related desynchronisation (ERD) in the alpha band (8-13 Hz) and an event-related synchronisation (ERS) in the gamma band (55-70 Hz). We show, using SPMs and virtual electrode traces, the spatio-temporal covariance of these effects with the visual BOLD response. Comparisons between MEG and fMRI data sets generally focus on the relationship between the BOLD response and the transient evoked response. Here, we show that the stationary field and changes in oscillatory power are also important contributors to the BOLD response, and should be included in future studies on the relationship between neuronal activation and the haemodynamic response.

Adult↗
PubMed2005

Dextromethorphan to dextrorphan urinary metabolic ratio does not reflect dextromethorphan oral clearance.

Dextromethorphan urinary metabolic ratio is widely used to determine the CYP2D6 phenotype, but its utility to reflect subtle differences in catalytic activity is unclear. We evaluated the capability of dextromethorphan urinary metabolic ratio to predict dextromethorphan oral clearance as a measure of CYP2D6 activity. Data from 10 healthy extensive metabolizers of CYP2D6 were given 30 mg of dextromethorphan hydrobromide orally on two occasions. Blood and urine samples were collected for 72 h. Dextromethorphan and dextrorphan were determined in urine by high-performance liquid chromatography with fluorescence detection and in serum by liquid chromatography-mass spectrometry. The urinary metabolic ratio was very weakly correlated with dextromethorphan oral clearance (r = 0.24; p = 0.04). In contrast, the dextromethorphan oral clearance was highly correlated with the dextromethorphan to dextrorphan area under the concentration-time curve ratio (r = 0.84; p = 0.005) and the 3-h (r = 0.60; p = 0.003), 4-h (r = 0.72, p < 0.001), 6-h (r = 0.67; p < 0.001), and 8-h (r = 0.74; p < 0.001) dextromethorphan to dextrorphan serum ratios. Assuming an effect size of 30%, the number of volunteers required for crossover and cross-sectional studies using the urinary metabolic ratio as the CYP2D6 index was calculated to be 56 and 524, respectively, whereas 14 and 60 subjects are needed if oral clearance is used. Considering the required sample size and the low correlation with oral clearance, urinary metabolic ratio is not recommended as the primary outcome variable in studies requiring the detection of modest changes in CYP2D6 activity.

Administration, Oral↗
PubMed2005

Effect of cirrhosis and liver transplantation on the gender difference in QT interval.

The effect of gender on the QT interval in patients with cirrhosis before and after liver transplantation and the relation between the QT interval and changes in gender hormones after liver transplantation were assessed. The study showed that (1) physiologic gender difference in the QTc interval is abolished in cirrhosis, and it is not restored after liver transplantation, and (2) gender hormone concentrations had no effect on the QTc interval.

Adolescent↗
PubMed2005

Differential mechanism-based inhibition of CYP3A4 and CYP3A5 by verapamil.

The genetic basis for polymorphic expression of CYP3A5 has been recently identified, but the significance of CYP3A5 expression is unclear. The purpose of this study is to quantify the capability of verapamil, a mechanism-based inhibitor of CYP3A, and its metabolites to inhibit the activities of CYP3A4 and CYP3A5, and to determine whether CYP3A5 expression in human liver microsomes alters the inhibitory potency of verapamil. Testosterone 6beta-hydroxylation or midazolam 1'-hydroxylation was used to quantify CYP3A activity. The possibility that verapamil and its metabolites form metabolic-intermediate complex (MIC) with CYP3A was assessed using dual beam spectrophotometry. Verapamil and N-desalkylverapamil (D617) were found to have little inhibitory effect on cDNA-expressed CYP3A5 activity and did not form a MIC with cDNA-expressed CYP3A5 as indicated by the appearance of the characteristic peak at 455 nm. At 50 microM, norverapamil showed time-dependent inhibition of CYP3A5 (30%), but to a much lesser extent compared with that of CYP3A4 (80%). The estimated values of the inactivation parameters k(inact) and K(I) of norverapamil were 4.53 microM and 0.07 min(-1) for cDNA-expressed CYP3A5, and 10.3 microM and 0.30 min(-1) for cDNA-expressed CYP3A4. Human liver microsomes that expressed CYP3A5 were less inhibited by both verapamil and norverapamil. The inactivation efficiency of verapamil and norverapamil was 30 times and 45 times lower, respectively, for CYP3A5-expressing microsomes compared with CYP3A5-non-expressing microsomes. These findings indicate that the presence of variable CYP3A5/CYP3A4 expression in the liver may contribute to the interindividual variability associated with verapamil-mediated drug interactions.

Blotting, Western↗
PubMed2005

Activity of CYP2E1 and CYP3A enzymes in adults with moderate alcohol consumption: a comparison with nonalcoholics.

Alcohol consumption is known to induce hepatic CYP2E1 activity, but its effect on hepatic and intestinal CYP3A in humans is not known. We have conducted a study to compare the CYP2E1 and CYP3A activities in 20 individuals with moderate alcohol consumption and 20 gender-, race-. and body mass index (BMI)-matched nonalcoholics. Intravenous and oral midazolam (MDZ) clearances were used to measure the in vivo CYP3A activity, and chlorzoxazone (CHZ) oral clearance was used to assess in vivo CYP2E1 activity. Furthermore, we assessed the relationship between hepatic CYP2E1 and CYP3A activities and their messenger RNA (mRNA) expression in the peripheral lymphocytes. The systemic clearance (CL) of MDZ was not different between alcoholics (36.9 +/- 12 L/hr) and nonalcoholics (36.6 +/- 14.1; P = .9). The oral availability of MDZ was significantly lower in alcoholics than in the nonalcoholics (0.28 +/- .09 vs. 0.38 +/- .17, respectively, P = .03). The maximum serum concentration after oral midazolam dosing was significantly different between the 2 groups. CHZ CL was significantly higher in alcoholics than in nonalcoholics (31.5 +/- 11.9 vs. 23.4 +/- 8.7 L/hr, P < 0.05). CYP3A4 and CYP2E1 mRNA levels were not significantly different between the groups, and no correlation was observed between lymphocyte CYP mRNA and in vivo CYP activity. In conclusion, in individuals with moderate alcohol consumption, there was no alteration in the hepatic CYP3A activity, but the reduced midazolam oral bioavailability suggests that moderate alcohol consumption may cause intestinal CYP3A induction. Lymphocyte CYP2E1 and CYP3A4 mRNA levels did not correlate with CYP2E1 and CYP3A activities.

Adult↗
PubMed2005

Distinct contrast response functions in striate and extra-striate regions of visual cortex revealed with magnetoencephalography (MEG).

OBJECTIVE: To spatially and temporally characterise the cortical contrast response function to pattern onset stimuli in humans. METHODS: Magnetoencephalography (MEG) was used to investigate the human cortical contrast response function to pattern onset stimuli with high temporal and spatial resolution. A beamformer source reconstruction approach was used to spatially localise and identify the time courses of activity at various visual cortical loci. RESULTS: Consistent with the findings of previous studies, MEG beamformer analysis revealed two simultaneous generators of the pattern onset evoked response. These generators arose from anatomically discrete locations in striate and extra-striate visual cortex. Furthermore, these loci demonstrated notably distinct contrast response functions, with striate cortex increasing approximately linearly with contrast, whilst extra-striate visual cortex followed a saturating function. CONCLUSIONS: The generators that underlie the pattern onset visual evoked response arise from two distinct regions in striate and extra-striate visual cortex. SIGNIFICANCE: The spatially, temporally and functionally distinct mechanisms of contrast processing within the visual cortex may account for the disparate results observed across earlier studies and assist in elucidating causal mechanisms of aberrant contrast processing in neurological disorders.

Adult↗
PubMed2005

Inhibition of human intestinal wall metabolism by macrolide antibiotics: effect of clarithromycin on cytochrome P450 3A4/5 activity and expression.

BACKGROUND: Clarithromycin increases both hepatic and intestinal availability of the selective cytochrome P450 (CYP) 3A probe midazolam. This study was designed to identify determinants of variability in the extent of intestinal wall CYP3A inhibition by clarithromycin, such as CYP3A5 genotype, and the mechanism of inhibition. METHODS: Ten healthy volunteers received 500 mg oral clarithromycin twice a day for 7 days. Before and after administration of clarithromycin, small-bowel mucosal biopsy specimens were obtained endoscopically. Intestinal CYP3A activity was determined from the rate of 1'-hydroxymidazolam and 4-hydroxymidazolam formation by incubation of small-bowel homogenate with midazolam (25 micromol/L) and NADPH for 5 minutes. Intestinal CYP3A4 and CYP3A5 messenger ribonucleic acid was quantified by real-time reverse transcriptase-polymerase chain reaction. Intestinal CYP3A4 and CYP3A5 protein concentrations were determined by immunoblotting. Serum and homogenate concentrations of midazolam, clarithromycin, and metabolites were determined by liquid chromatography-mass spectrometry. CYP3A5 genotype was determined by real-time polymerase chain reaction. RESULTS: The formation of 1'-hydroxymidazolam (1.36 +/- 0.46 pmol . min(-1) . mg(-1) at baseline versus 0.35 +/- 0.16 pmol . min(-1) . mg(-1) after administration) and 4-hydroxymidazolam (0.39 +/- 0.12 pmol . min(-1) . mg(-1) at baseline versus 0.12 +/- 0.05 pmol . min(-1) . mg(-1) after administration) was significantly (P < .001) reduced after clarithromycin administration. Clarithromycin administration did not result in a significant change in intestinal CYP3A4 and CYP3A5 messenger ribonucleic acid and protein expression. All subjects had detectable serum clarithromycin concentrations after 7 days of clarithromycin (3.71 +/- 2.43 micromol/L). The mean concentration of clarithromycin in the intestinal biopsy homogenate was 1.2 +/- 0.7 nmol/L (range, 0.42-2.39 nmol/L). Compared with CYP3A5 nonexpressers, subjects with at least 1 CYP3A5*1 allele (CYP3A5 expressers) had greater inhibition of intestinal CYP3A activity after treatment with clarithromycin. There was a strong linear relationship between the decrease in intestinal CYP3A activity and baseline catalytic activity (R(2) = 0.9). CONCLUSION: Baseline intestinal activity of CYP3A4 was a key determinant of variability of the inhibitory effect of clarithromycin among individuals. CYP3A5*1 alleles were associated with greater baseline intestinal CYP3A activity and, therefore, greater extent of inhibition. The primary in vivo mechanism was not rapidly reversible competitive or irreversible inhibition but was likely formation of metabolic intermediate complexes.

Administration, Oral↗
PubMed2005

Effect of rosiglitazone on serum liver biochemistries in diabetic patients with normal and elevated baseline liver enzymes.

OBJECTIVES: Thiazolidinediones (TZD) are recommended to be used cautiously in diabetics with mild elevations in liver enzymes and not to be used in those with alanine aminotransferase>2.5 upper limit normal (ULN). However, studies are not adequate that evaluated the risk of TZD hepatotoxicity in diabetics with elevated liver enzymes. We conducted a study to test if diabetics with elevated liver enzymes have increased risk for hepatotoxicity from rosiglitazone (only TZD available on our formulary). METHODS: This study consisted of two cohorts of patients prescribed rosiglitazone since January 2000. Cohort 1: 210 diabetics with elevated baseline liver enzymes (aspartate aminotransferase (AST)>40 IU/L and/or alanine aminotransferase (ALT)>35 IU/L) who received rosiglitazone, and cohort 2:628 diabetics with normal liver enzymes who received rosiglitazone. Elevations in liver biochemistries over a 12-month period after initiating rosiglitazone were characterized into mild to moderate or severe elevations and into "Hy's rule" based on published criteria. RESULTS: Compared to cohort 2, patients in cohort 1 did not have higher incidence of mild to moderate (10% vs 6.6%, p=0.2) or severe elevations (0.9% vs 0.6%, p=0.9) in liver biochemistries. Similarly, the incidence of liver biochemistry abnormalities meeting the Hy's Rule was statistically not different between the two cohorts (0% vs 0.3%, p=0.9). The frequency of discontinuing rosiglitazone therapy during the follow-up was similar between cohorts 1 and 2 (8.6% vs 8.1%, p=1.0). CONCLUSIONS: These results suggest that diabetics with elevated baseline liver enzymes do not have a higher risk of hepatotoxicity from rosiglitazone than those with normal enzymes.

Alanine Transaminase↗
PubMed2004

Association between the CYP3A5 genotype and blood pressure.

We tested the hypothesis that the presence of a CYP3A5*1 allele is associated with increases in blood pressure in 2 studies of subjects with a total of 683 participants. The first study involving 271 subjects was part of a longitudinal study conducted at Indiana University Medical Center that consisted of 2 phases. The first phase studied the relationship of salt sensitivity with blood pressure, whereas the second phase, conducted approximately 26 years later, studied the relationship between blood pressure, carbohydrate intolerance, and vascular compliance in the same subjects. The second study was a cross-sectional evaluation of 412 normotensive and hypertensive subjects conducted at the University of California San Diego. The second study (Mantel-Haenszel chi(2) test; P=0.05) showed that a greater proportion of black participants with poor blood pressure control had CYP3A5*1/*1 genotype. Evaluation of the untreated blood pressure from phase 1 of the first study showed that the blacks with CYP3A5*3/*3 (146+/-35 mm Hg) had a higher systolic blood pressure than those with the *1/*3 (119+/-14.1 mm Hg; P=0.0006) and *1/*1 (125+/-17.4 mm Hg; P=0.009) genotypes. For blacks in study 2, the CYP3A5*1 allele was more common in hypertensives (Fisher exact test; P=0.025) than normotensives. In whites there was no association between CYP3A5 genotype and blood pressure in either study. We conclude that although untreated blood pressure may be higher in blacks with the CYP3A5*3/*3 genotype, the CYP3A5*1 allele may be associated with hypertension that is more refractory to treatment in this ethnic group.

Alleles↗
PubMed2004

Mechanism-based inactivation of CYP3A by HIV protease inhibitors.

Human immunodeficiency virus (HIV) protease inhibitors (PIs) are inhibitors of CYP3A enzymes, but the mechanism is poorly defined. In this study, time- and concentration-dependent decreases in activity as defined by maximum rate of inactivation (k(inact)) and inhibitor concentration that gives 50% maximal inactivation (K(I)) of CYP3A by amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir were quantified using testosterone 6beta-hydroxylation as a marker for CYP3A activity with recombinant CYP3A4(+b(5)), recombinant CYP3A5, and pooled human liver microsomes (HLMs). All the PIs, except indinavir, displayed inactivation with CYP3A4(+b(5)) and HLMs. Ritonavir was the most potent (K(I) = 0.10 and 0.17 microM) and demonstrated high k(inact) values (0.32 and 0.40 min(-1)) with both CYP3A4(+b(5)) and HLMs. Ritonavir was not significantly depleted by high-affinity binding with CYP3A4(+b(5)) and confirmed that estimation of reversible inhibition was confounded with irreversible inhibition. For CYP3A5, nelfinavir exhibited the highest k(inact) (0.47 min(-1)), but ritonavir was the most potent (K(I) = 0.12 microM). Saquinavir and indinavir did not show time- and concentration-dependent decreases in activity with CYP3A5. Spectrophototmetrically determined metabolic intermediate complex formation was observed for all of the PIs with CYP3A4(+b(5)), except for lopinavir and saquinavir. The addition of nucleophilic and free aldehyde trapping agents and free iron and reactive oxygen species scavengers did not prevent inactivation of CYP3A4(+b(5)) by ritonavir, amprenavir, or nelfinavir, but glutathione decreased the inactivation by saquinavir (17%) and catalase decreased the inactivation by lopinavir (39%). In conclusion, all the PIs exhibited mechanism-based inactivation, and predictions of the extent and time course of drug interactions with PIs could be underestimated if based solely on reversible inhibition.

Aldehydes↗