Pharmacokinetic equivalence of 5(ethyl(2H)5)- and unlabelled phenobarbitone.
The present study shows the absence of in vivo pharmacokinetic isotope effect on phenobarbitone (PB) C5-ethyl deuteration (PBd5) following oral administration to man of equimolar PB/PBd5 mixtures (0.40 mmol each). Plasma PB and PBd5 (17 days) and urine PB, PBd5 and parahydroxy-metabolites (PBOH, PBHOd5) levels were determined by GC-MS. Isotope effect research includes comparison of pharmacokinetic parameters, study of time-dependence of isotope ratios (IRs) in plasma and urine (linearity test), comparison of IRs between samples and administered mixtures (Mann Whitney's test) and comparison of PBOH/PBOHd5 ratios before and after urine enzymatic hydrolysis (Student's two tailed t-test). No significant isotope effect was observed on pharmacokinetic parameters, PB hydroxylation or PBOH conjugation (x less than or equal to 5%); which the absence of pentadeuteration-induced alteration in PB's HSA binding parameters (binding mode, Ka, N) corroborates (x less than or equal to 5%). These results establish bioequivalence of PB and PBd5; the latter can be used with benefit in stable-isotope clinical pharmacology (steady state pharmacokinetics, drug interactions...) investigations as well as bioavailability studies of PB preparations.
Benchekroun
Y
Y
Laboratoire D'Etudes Analytiques Et Cinetiques Du Medicament, Faculte De Pharmacie, Lyon, France.
Ribon
B
B
Falconnet
J B
JB
Cherrah
Y
Y
Brazier
J L
JL
D000328:Adult; D003903:Deuterium; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D006900:Hydroxylation; D007202:Indicators and Reagents; D008297:Male; D010634:Phenobarbital / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D011485:Protein Binding; D012709:Serum Albumin / Q000378:metabolism
D007202:Indicators and Reagents; D012709:Serum Albumin; D003903:Deuterium; D010634:Phenobarbital