Biomedical subjects

P d'Athis

Publications and source records attributed to P d'Athis.

At least 19 recordsLinked to original sources

PubMed2003

Inhibitory effect of stiripentol on carbamazepine and saquinavir metabolism in human.

AIMS: To characterize the in vitro and in vivo inhibitory effect of stiripentol, a new anticonvulsant, on the metabolism of carbamazepine and saquinavir, which are substrates of CYP3A4. METHODS: Human liver microsomes and cDNA-expressed CYP enzymes were used for the in vitro experiments. Pharmacokinetic data from epileptic children and healthy adults were used for the carbamazepine and saquinavir in vivo studies, respectively. RESULTS: Carbamazepine biotransformation to its 10,11-epoxide by human liver microsomes (Vmax = 10.3 nmol min(-1) nmol(-1) P450, apparent Km = 362 microm), cDNA-expressed CYP3A4 (Vmax = 1.17 nmol min(-1) nmol(-1) P450, apparent Km = 119 microm) and CYP2C8 (Vmax = 0.669 nmol min(-1) nmol(-1) P450, apparent Km = 757 microm) was inhibited by stiripentol (IC50 14, 5.1, 37 microM and apparent Ki 3.7, 2.5, 35 microm, respectively). Saquinavir biotransformation to its major metabolite M7 by human liver microsomes (Vmax = 5.7 nmol min(-1) nmol(-1) P450, apparent Km = 0.79 microm) was inhibited by stiripentol (IC50 163 microM, apparent Ki 86 microm). In epileptic children treated with carbamazepine and stiripentol, the plasma concentration ratio of carbamazepine epoxide/carbamazepine was decreased by 65%. The in vivo apparent Ki for stiripentol ranged from 10.5 to 41.4 microm. The pharmacokinetics of saquinavir was not modified by stiripentol in healthy adults. The 95% confidence intervals for the difference for Cmax and AUC of saquinavir between the placebo and stiripentol phase were (-39.8, 39.8) and (-33.2, 112), respectively. CONCLUSIONS: These results showed that stiripentol was a weak inhibitor of saquinavir metabolism both in vitro and in vivo. In contrast, stiripentol is a potent inhibitor of carbamazepine 10,11-epoxide formation in vitro and in vivo in epileptic patients.

Adolescent↗

PubMed2001

Protective effect of stiripentol on acetaminophen-induced hepatotoxicity in rat.

Acetaminophen (APAP) is mainly eliminated at a therapeutic dose through glucuronidation and sulfatation and a small fraction is oxidized by cytochromes P450 (CYP) 2E1, 3A4, and 1A2 to N-acetyl-p-benzoquinone-imine (NAPQI), a highly reactive metabolite further conjugated with glutathione into APAP-GSH, and then metabolized to APAP-cystein and APAP-mercapturate excreted in urine. After APAP overdose, the glucuronidation and sulfatation pathways are saturated and the production of NAPQI increases, causing hepatic injury. Stiripentol (STP); (200 mg/kg), an anticonvulsant drug inhibitor of CYP1A2 and CYP3A4 in vivo in humans was tested against APAP-induced toxicity in rat in comparison with N-acetylcysteine (NAC; 100 mg/kg). The mortality rates 24 h after APAP overdose (2 x 500 mg/kg) were 63% (control), 38% (NAC), 0% (STP), and 4% (STP + NAC). The mean plasma transaminase concentrations 5 and 24 h after overdose were significantly higher in control than in STP and NAC groups. The percentage of rats without microscopic liver necrosis 5 h after APAP overdose was significantly higher in rats receiving STP (100%), NAC (83%), or STP + NAC (83%) than controls (42%). In another experiment, four similar groups were administered 50 mg/kg APAP. Plasma AUC(0-5 h) for APAP-GSH, APAP-cystein, and APAP-mercapturate as well as urine APAP-mercapturate mean amounts were significantly lower in STP animals than in the other groups. STP (200 mg/kg) inhibited NAPQI synthesis through CYP inhibition, thus preventing both liver necrosis and mortality in rats.

Acetaminophen↗

PubMed2001

S15176 and S16950 interaction with Cyclosporin A antiproliferative effect on cultured human lymphocytes.

S15176 and S16950 are trimetazidine derivatives that antagonize more strongly than the parent drug mitochondrial toxicity, which leads to cellular hypoxia and nephrotoxicity in kidneys experimentally exposed to cyclosporin A. We have investigated whether every derivative might interact or not with the inhibitory effect of Cyclosporin A on the proliferation of cultured human lymphocytes. S15176 significantly increased the antilymphoproliferative effect of Cyclosporin A, whereas S15176 by itself neither displayed any antilymphoproliferative effect, nor did it induce any apoptotic process in cultured human lymphocytes. The effect of S16950 was not significant.

Adult↗

PubMed2001

Isoniazid pharmacokinetics in children according to acetylator phenotype.

The pharmacokinetics of isoniazid (INH) was studied in children (0-196 months old) according to their acetylator phenotype, estimated from the metabolic acetyl INH/INH molar plasma concentration ratio (MR) measured 3 h after INH oral administration. There were 17 slow (MR < 0.48) and 17 fast acetylators (MR > or = 0.48). The mean apparent plasma clearance was significantly lower, the mean apparent volume of distribution higher and the half-life longer in the slow acetylator group (C1, 0.298 +/- 0.099 L/h/kg; Vd, 1.56 +/- 0.65 L/kg; t1/2, 3.88 +/- 01.89 h) than in the fast acetylator group (Cl, 0.528 +/- 0.234 L/h/kg; Vd, 1.06 +/- 0.45; t1/2, 1.64 +/- 1.1 h). The half-life decreased with age. An impaired isoniazid elimination was suggested in children less than three months old, which may be in favour of an individual dose adjustment in this population.

Acetylation↗

PubMed2001

Antipyretic efficacy of an initial 30-mg/kg loading dose of acetaminophen versus a 15-mg/kg maintenance dose.

OBJECTIVE: To compare the antipyretic efficacy of an initial 30-mg/kg acetaminophen loading dose versus a 15-mg/kg maintenance dose. METHODS: A double-blind, parallel-group, randomized clinical trial was conducted. A total of 121 febrile (rectal temperature between 39 degrees C and 40 degrees C) but otherwise healthy outpatients who were 4 months to 9 years of age and weighed 4 to 26 kg were assigned randomly to 1 of the dose groups: 15 mg/kg (n = 62) and 30 mg/kg (n = 59). RESULTS: In an "intention to treat" analysis, the time to obtain a temperature lower than 38.5 degrees C was significantly shorter in the 30-mg/kg than in the 15-mg/kg group (110 +/- 94 minutes vs 139 +/- 113 minutes). The maximum temperature decrease was significantly higher in the 30-mg/kg than in the 15-mg/kg group (2.3 +/- 0.7 degrees C vs 1.7 +/- 0.6 degrees C). Duration of rectal temperature below 38.5 degrees C was significantly longer in the 30-mg/kg than in the 15-mg/kg group (250 +/- 92 minutes vs 185 +/- 121 minutes, respectively). Adverse events were reported in 6 children in the 30-mg/kg group compared with 5 in the 15-mg/kg group (hyperthermia, hypothermia, vomiting). The difference was not statistically significant. CONCLUSION: An initial 30-mg/kg acetaminophen loading dose seemed to be more effective in reducing fever than a 15-mg/kg maintenance dose. No difference was observed regarding clinical tolerance. These data suggest that acetaminophen treatment of fever may be more efficient in an initial loading dose.

Acetaminophen↗

PubMed2000

Stiripentol in severe myoclonic epilepsy in infancy: a randomised placebo-controlled syndrome-dedicated trial. STICLO study group.

BACKGROUND: Stiripentol is an inhibitor of cytochrome P450 that showed antiepileptic efficacy in severe myoclonic epilepsy in infancy (SMEI) in association with clobazam and valproate in an open study. To confirm these results, 41 children with SMEI were included in a randomised, placebo-controlled, add-on trial. METHODS: After a baseline period of 1 month, placebo (n=20) or stiripentol (n=21) was added to valproate and clobazam during a double-blind period of 2 months. Patients then received stiripentol in an open fashion. Responders were defined as having more than 50% reduction in the frequency of clonic (or tonic-clonic) seizures during the second month of the double-blind period compared with baseline. FINDINGS: 15 (71%) patients were responders on stiripentol (including nine free of clonic or tonic-clonic seizures), whereas there was only one (5%) on placebo (none were seizure free; stiripentol 95% CI 52.1-90.7 vs placebo 0-14.6). The 95% CI of the difference was 42.2-85.7. Percentage of change from baseline was higher on stiripentol (-69%) than on placebo (+7%), p<0.0001. 21 patients on stiripentol had moderate side-effects (drowsiness, loss of appetite) compared with eight on placebo, but side-effects disappeared when the dose of comedication was decreased in 12 of the 21 cases. INTERPRETATION: This controlled trial shows the antiepileptic efficacy, of add-on stiripentol in children with SMEI. The results also provide good reason to focus studies on a specific epilepsy syndrome-a small sample of patients is sufficient to show the efficacy that might have been missed in a heterogeneous population.

Anti-Anxiety Agents↗

PubMed2000

French multicenter randomized double-blind placebo-controlled trial on nebulized amiloride in cystic fibrosis patients. The Amiloride-AFLM Collaborative Study Group.

The effect of amiloride, a sodium channel blocker, has been evaluated in a multicenter randomized double-blind placebo-controlled trial in cystic fibrosis patients more than 5-years-old (n = 137) whose forced vital capacity (FVC), forced expiratory volume in 1 sec (FEV(1)), and forced mid-expiratory flow (FEF(25-75)) were not below 50%, 50%, and 30% of reference values, respectively. Patients were randomly allocated to two parallel groups. Sixty-four patients were chronically colonized with Pseudomonas aeruginosa; they received either amiloride or placebo as a nebulized solution three times daily for 6 months. Routine treatments were continued. Patients chronically colonized with Pseudomonas received nebulized colimycine twice a day for a month during the third and sixth months of treatment. Bronchopulmonary exacerbations were treated in the usual way. The effects of the amiloride treatment were assessed at the end of the 6-month treatment period. The effects on FVC and secondarily on FEV(1), FEF(25-75), the number of days on antibiotic therapy, the Shwachman score, a nutritional index (weight/height(2)), the change in sputum bacterial flora, and nocturnal cough were assessed. For the patients not chronically colonized with Pseudomonas, the effect of the treatment was also evaluated by counting chronic colonizations with pathogens appearing during the trial period. The present study failed to demonstrate any significant benefit of amiloride over placebo on FVC, FEV(1), and the other secondary endpoints in the studied population. Neither the chronically colonized, nor the noncolonized patients benefited. The confidence intervals of the differences between treatment groups indicated small differences that were most likely of no clinical significance. Complementary analyses taking into account the gender, the type of mutation, the subpopulations whose FVC and FEV(1) were below 80% of normal values at the beginning of the study, and also patients less than 10 years old, did not show any statistically or clinically significant improvements following amiloride therapy.

Administration, Inhalation↗

PubMed2000

Standing up from a chair as a dynamic equilibrium task: a comparison between young and elderly subjects.

The purpose of this study was to analyze and compare the features of center of mass (CoM) control along anterior/posterior axis in young and elderly subjects during sit-to-stand (STS). From a sitting position, seven healthy young subjects and seven healthy elderly subjects were asked to stand up from a chair under different experimental conditions (visual conditions: normal and blindfolded; speed: normal and as fast as possible). Analysis of results was based upon the concept of a "dynamic equilibrium area" (DEA), which in turn identified the dynamic limits of balance. The results showed that both the maximal CoM velocity in the horizontal axis and the CoM velocity at the instant of seat-off were found to be lower in elderly compared with young subjects. Concerning the maximal CoM velocity, the difference was increased under blindfolded condition. The position of CoM in the phase plane (i.e., velocity according to displacement) at the instant of seat-off was found to be shifted backward in elderly subjects. From these results we can deduce that age-related modifications can he observed in the control of the horizontal CoM motion during STS in healthy elderly subjects.

Adult↗

PubMed1999

Dose proportionality of reboxetine enantiomers in healthy male volunteers.

Reboxetine is a racemic mixture of FCE 22071 and FCE 21684 enantiomers. The pharmacokinetics of the enantiomers of reboxetine were observed to be linear in male healthy subjects (n = 6) after the administration of 1.5, 3, 4.5 mg dose of reboxetine as solutions. Kinetic analysis was based on chiral HPLC assay of the enantiomers in plasma collected up to 72 h after each administration. C(max) and AUC were more than double for FCE 22071 (C(max): 38.3+/-13.5, 76. 6+/-26.3, 99.8+/-24.1 ng/mL and AUC(infinity): 605.8+/-233.2, 1288. 3+/-796.4, 1780.7+/-669.3 ng. h/mL for 1.5, 3, 4.5 mg, respectively) than for FCE 21684 (C(max): 15.2+/-5.3, 34.6+/-14.0, 43.1+/-12.3 ng/mL and AUC(infinity): 247.0+/-103.9, 529.1+/-278.4, 773.0+/-355.3 ng. h/mL), whatever the administered dose. The half-lives of the enantiomers were similar (FCE 22071: 13.1, 11.0, 12.6 h and FCE 21684: 12.8, 11.2, 12.2 h after 1.5, 3, 4.5 mg, respectively) and not substantially affected by the dose level.

Administration, Oral↗

PubMed1999

Falsely elevated intraocular pressure due to increased central corneal thickness.

PURPOSE: To evaluate whether ocular hypertensive subjects have a higher central corneal thickness than other individuals. METHODS: In this prospective study, 48 subjects with ocular hypertension, 63 patients with open-angle glaucoma, 56 nonglaucomatous patients with diabetes mellitus, and 106 control subjects were evaluated. Corneal thickness was measured by ultrasound pachymetry, and intraocular pressure was determined by Goldmann applanation tonometry. RESULTS: Central corneal thickness was significantly higher in the ocular hypertensive subjects, mean +/- S.D., 592+/-39 microm, than in the patients with glaucoma (536+/-34 microm), the nonglaucomatous patients with diabetes mellitus (550+/-31 microm), and the normal subjects (545+/-33 microm), P<0.001. The three latter groups did not vary significantly in central corneal thickness, P>0.05. CONCLUSION: In some individuals with increased transcorneal measurements of intraocular pressure, the cornea is thicker than in subjects with normal intraocular pressure readings or patients with glaucoma. It suggests that in ocular hypertensive subjects, corneal pachymetry should be performed to rule out an abnormally thick cornea as a reason for falsely high measurements of intraocular pressure.

Adolescent↗

PubMed1999

Pharmacokinetics and tolerance of flunitrazepam in neonates and in infants.

OBJECTIVE: To study the pharmacokinetics of flunitrazepam (used for sedation in neonates and infants), to determine the influence of both gestational and postnatal age on the pharmacokinetic parameters, and to analyze the relationship between the hemodynamic parameters and flunitrazepam plasma concentration. METHODS: Flunitrazepam was infused for 20 minutes as a single dose (0.2 mg x kg(-1)) and as multiple doses (0.1 mg x kg(-1)). Six to eight 1-mL blood samples were collected per patient. Flunitrazepam plasma concentration was measured by gas chromatography-mass spectrometry. RESULTS: Thirty-one patients (25 neonates and six infants) were included in the study. Only three of them received multiple doses. After the single dose (n = 28), half-life was 22.6 +/- 7.3 hours, clearance was 0.15 +/- 0.14 L x kg x h(-1), and volume of distribution was 4.6 +/- 4.1 L x kg(-1) (mean +/- SD). Plasma clearance and volume of distribution significantly increased with postnatal age (P < .05), but no pharmacokinetic parameter varied significantly with gestational age. Diastolic blood pressure significantly decreased with increasing flunitrazepam plasma concentrations (P < .05). CONCLUSION: Postnatal age but not gestational age influenced flunitrazepam pharmacokinetic parameters in neonates and infants. Diastolic blood pressure was inversely correlated to flunitrazepam plasma concentration.

Age Factors↗

PubMed1999

Stiripentol: efficacy and tolerability in children with epilepsy.

PURPOSE: Stiripentol (STP) is a new antiepileptic drug (AED) that inhibits cytochrome P450, resulting in increased plasma concentrations of concomitant AEDs. The efficacy and tolerability of STP as an add-on therapy in children were assessed. METHODS: Two hundred twelve patients with refractory epilepsy, aged from 1 month to 20.5 years, received STP either in a single-blind, placebo-controlled trial (108 patients) or in a further open trial (104 other patients selected by epilepsy syndrome for possible efficacy based on the results of the previous trial). RESULTS: Among the 97 patients who could be analyzed for efficacy in the placebo-controlled study, the median seizure frequency was lower at 3 months with STP than with the placebo (p<0.0001); 49% responded to the drug, including 10% who became seizure free. Patients with partial epilepsy had the highest response rate (57%). Results were confirmed in the open study where 68% of the 91 patients receiving STP responded at 3 months. These patients were mainly those with partial epilepsy (73%) who were receiving carbamazepine (CBZ) (75%) as comedication (p<0.001). Ten of the 20 children with severe myoclonic epilepsy in infancy also responded with clobazam (CLB) as comedication. Efficacy was sustained long term in 74% of the 94 patients still receiving STP at a mean 30-month follow-up. Adverse events were reported in 48% of the 212 patients, mainly anorexia and loss of weight, but these events required STP discontinuation in only nine cases. Side effects were minimized in the open trial by optimizing the dose of comedication. CONCLUSIONS: STP seems to be a promising add-on drug, particularly when combined with CBZ in patients with partial childhood epilepsy refractory to vigabatrin (VGB) and with CLB in patients with severe myoclonic epilepsy in infancy.

Adolescent↗

PubMed1999

Can a database be anonymous?

Sensitive data are most often indirectly identifiable and so need to be rendered anonymous in order to ensure privacy. Statistical methods to provide anonymity require data perturbation and so generate data processing difficulties. Encryption methods, while preserving confidentiality, do not require data modification.

Computer Communication Networks↗

PubMed1998

[Retrospective survey of fluoroquinolone use in children].

BACKGROUND: Fluoroquinolones (FQ) are contraindicated in children because of the risk of cartilage damage. POPULATION AND METHODS: A retrospective survey concerning the use of FQ in children during the first 6 months of 1993 was organized in 1994. One hundred and sixty-seven Heads of pediatric departments were questioned. RESULTS: One hundred and fifty (90%) of those surveyed responded: 62 (41.3%) were FQ prescribers, 83 (55.3%) were non prescribers and five (3.4%) were not able to answer. Among the 62 prescribers of FQ, 17 departments (27%) were not able to indicate the number of prescriptions and 45 departments (73%) reported one to 75 prescriptions during the study period. Twenty-one departments out of the 45 were not able to identify the children treated with FQ. We obtained a group of 104 children aged 9.0 +/- 5.0 years (mean +/- standard deviation [SD]), treated with 165 courses of FQ during 20 +/- 45 days (1-535 days) with concomitant treatments for 132/165 courses (80%). Fifty children (48%) were suffering from cystic fibrosis, 37 children (36%) were not, and, in 17, the diagnosis was not determined (16%). The FQ treatment administered either orally (73%) or intravenously (26%) was ciprofloxacin in 69% of the courses with a 25.1 +/- 7.0 mg/kg/day oral dose (mean +/- SD dose), and a 23.5 +/- 11.4 mg/kg/day intravenous dose, pefloxacin in 23 courses/165 (14%) with a 17.2 +/- 3.8 mg/kg/day dose, ofloxacin in 15 courses/165 (9%) with a 21.0 +/- 11.9 mg/kg/day dose, norfloxacin in 13 courses/165 (8%) with a 25.6 +/- 7.5 mg/kg/day dose. Twenty-one adverse events were reported in 17 children (16%) (11 of them with cystic fibrosis). These were cutaneous events (photosensitivity, cutaneous eruption) in eight courses, rheumatologic events (arthralgia, arthritis) in seven courses and gastrointestinal events (nausea, vomiting, diarrhea) in three courses. CONCLUSION: This survey shows that FQ are prescribed in children although their use is not approved in this age group and that numerous side effects have been recorded. The absence of exhaustive information (due to the retrospective nature of the survey) and the difficulties in interpreting the side effects for which validity and causal assessment have not been worked out according to a standardized method and in the absence of a control group stress the need for a prospective study.

Adolescent↗

PubMed1998

Isoniazid dose adjustment in a pediatric population.

This retrospective analysis was designed to evaluate the inactivation index (I3) method used to adjust the isoniazid dose during long-term administration in a pediatric population. Before starting on antituberculosis therapy, sixty-one children received one 10 mg.kg-1 isoniazid test-dose (D). The isoniazid and acetyl isoniazid concentrations were measured by high-performance liquid chromatography on a plasma sample collected 3 hours (C3h) after administration. The patients were separated into slow and fast acetylator groups according to the metabolic ratio. The dose adjustment method using the I3 is based on the assumption that there is a linear correlation between C3h and D [C3h = (I3 x D) - 0.6] in which the slope is I3 and the Y intercept is equal to -0.6 mg.l-1. I3 was determined from a single plasma concentration determination and used to calculate the dose recommended to obtain a desired C3h equal to 1.5 micrograms.ml-1: recommended dose (mg.kg-1) = (1.5 + 0.6)/I3.I3 was significantly higher in the slow acetylator group (0.55 +/- 0.16) than in the fast one (0.26 +/- 0.13), which leads us to recommend a significantly lower dose in the slow acetylator group (4.2 +/- 1.5 mg.kg-1) than in the fast one (10.3 +/- 4.6 mg.kg-1). The data obtained in a subgroup of 21 patients who had at least three consecutive determinations of C3h after different dosages allowed us to verify that there was a linear correlation between C3h and the dose. The mean slope of the correlation lines in that subgroup was 0.61 +/- 0.25 and the 95% confidence interval of the estimated Y-intercept include the theoretical value of -0.60, which shows that our data are consistent with those previously reported in adults. The percentage of patients with a C3h plasma concentration within the expected range (1.5 +/- 0.5 micrograms.ml-1) was significantly higher (69%) in those whose dose was derived from the calculation than in the others (25%). Within each acetylator group, the range of the recommended dose varied widely, and these results emphasize the usefulness of individual dose adjustment based on the inactivation index method.

Adolescent↗

PubMed1998

Ligand specificity of the genetic variants of human alpha1-acid glycoprotein: generation of a three-dimensional quantitative structure-activity relationship model for drug binding to the A variant.

Human alpha1-acid glycoprotein (AAG) is a mixture of at least two genetic variants: the A variant and the F1 and/or S variant or variants, which are encoded by two different genes. In a continuation of previous studies indicating specific drug transport roles for each AAG variant according to its separate genetic origin, this work was designed to (1) determine the affinities of the two main gene products of AAG (i.e., the A variant and a mixture of the F1 and S variants) for 35 chemically diverse drugs and (2) to obtain meaningful 3D-QSARs for each binding site. Affinities were obtained by displacement experiments, leading to qualitative indications about binding site characteristics. In particular, drugs binding selectively to the A variant displayed some common structural features, but this was not seen for the F1*S variants. Three-dimensional QSAR analyses using the CoMFA method yielded a steric model for binding to the A variant, from which a simplified haptophoric model was derived. In contrast, no statistically sound model was found for the F1*S variants, possibly due (among other reasons) to an insufficient number of high affinity ligands in the set.

Alleles↗

PubMed1997

Urea removal by neonatal hemo(dia)filters in hyperazotemic rabbits.

OBJECTIVE: Comparison of three neonatal hemo(dia)filters (FH22, Gambro; Minifilter Plus, Amicon; Miniflow 10, Hospal) for removal of urea by venovenous hemofiltration (HF) and venovenous hemodiafiltration (HDF). DESIGN: Filters were successively used for HF with two different blood flows (Qb = 8.3 and 16.6 ml/ min) and for HDF with the two different blood flows and four dialysate flows (Qd = 0.5, 1.0, 2.0, and 3.0 l/h). SUBJECTS: 21 anesthetized adult New Zealand White rabbits infused with urea. MAIN RESULTS: Urea clearance was significantly increased by HDF compared to HF regardless of blood flow, dialysate flow, and the hemo (dia)filter type except in the FH22 group, when blood flow was high and dialysate flow was 0.5 or 1.0 l/h. The FH22 filter allowed the best urea clearance during HF at high blood flow. During the HDF procedures, the Miniflow 10 allowed the highest urea clearance regardless of blood flow and dialysate flow.

Analysis of Variance↗

PubMed1997

Influence of stiripentol on cytochrome P450-mediated metabolic pathways in humans: in vitro and in vivo comparison and calculation of in vivo inhibition constants.

OBJECTIVE: The spectrum of cytochrome P450 inhibition of stiripentol, a new anticonvulsant, was characterized in vitro and in vivo. METHODS: Stiripentol was incubated in vitro with (R)-warfarin, coumarin, (S)-warfarin, (S)-mephenytoin, bufuralol, p-nitrophenol, and carbamazepine as probes for CYPs 1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A4, respectively. Caffeine demethylation and the 6 beta-hydroxycortisol/cortisol ratio were monitored in vivo before and after 14 days of treatment with stiripentol as measures of CYP1A2 and CYP3A4 activity, and dextromethorphan O- and N-demethylation were used to measure CYP2D6 and CYP3A4 activity, respectively. In vivo inhibition constants for CYP3A4 were calculated with use of data that previously documented the interaction between stripentol and carbamazepine. RESULTS: In vitro, stiripentol inhibited CYPs 1A2, 2C9, 2C19, 2D6, and 3A4, with inhibition constant values at or slightly higher than therapeutic (total) concentrations of stiripentol, but it did not inhibit CYPs 2A6 and 2E1 even at tenfold therapeutic concentrations. In vivo inhibition of caffeine demethylation and dextromethorphan N-demethylation were consistent with inhibition of CYP1A2 and CYP3A4, respectively. The 6 beta-hydroxycortisol/cortisol ratio did not provide a reliable index of CYP3A4 inhibition. Inhibition of CYP2D6-mediated O-demethylation was not observed in vivo. With use of carbamazepine, in vivo inhibition constants for CYP3A4 ranged between 12 and 35 mumol/L, whereas the corresponding in vitro value was 80 mumol/L. CONCLUSIONS: Stiripentol appears to inhibit several CYP450 enzymes in vitro and in vivo. In vivo inhibition constants show that stiripentol inhibition of CYP3A4 is linearly related to plasma concentration in patients with epilepsy.

Adult↗