Assessment of doxylamine influence on mixed function oxidase activity upon multiple dose oral administration to normal volunteers (original) (raw)
Related papers
Heterogeneous response of hepatic mixed function oxidases to chronic phenobarbital administration
Biochemical Pharmacology, 1979
Effects of chronic phenobarbital (PB) administration (75 mg/kg, p.o. for 59 days) on certain hepatic mixed function oxidases (HMFO) were investigated in male Sprague-Dawley rats to determine whether maximal induction is maintained throughout this period or whether further alterations occur in the inductive effect. As demonstrated by measurements of '"CO, excretion rates in breath after a single i.p. injection of [dimethyhunine-L4C]aminopyrine ([ r4C]aminopyrine), PB in the above dose for 7 days accelerated hepatic aminopyrine demethylation 92 per cent above control values. However, after 59 days of PB administration, 14C0, excretion was only 5 per cent above control values: thus, initial PB-induced enhancement of aminopyrine N-demethylation declined with time. Phenobarbital administration did not affect total (unlabeled) CO, output, indicating that decreased '4c0, excretion did not result from potential PB-induced reduction of CO, output. In contrast, total cytochrome P450 content and aniline hydroxylase activity remained elevated throughout the 59 days of PB treatment. Ethylmorphine N-demethylase activity and ammopyrine N-demethylase activity (using a 3.0 mM substrate concentration) remained elevated until 28 days of PB administration. after which time these activities decreased significantly (P < 0.05), finally reaching 7 1 and 83 per cent respectively, of peak activity. Kinetic analyses of aminopyrine N-demethylation
European Journal of Clinical Pharmacology, 1975
The 24 h urinary excretion of 6B-hydroxycortisol and D-glucaric acid, the plasma halflives and total clearances of aminopyrine, and serum gamma-glutamyl-transpeptidase activity have been measured in nineteen healthy male volunteers. The study was done double blind and was conducted as a test of induction of microsomal drug metabolizing enzymes during and after daily doses of 6 mg clemastine, 300 mg phenobarbital or a placebo. The urinary excretion of 6~-hydroxycortisol and D-glucaric acid was significantly increased in the phenobarbital group, the standard for induction. No changes were observed after treatment with clemastine or placebo. Phenobarbital also reduced the half life of aminopyrine, but it was not affected by clemastine or placebo. Gammaglutamyl-transpeptidase activity increased only in the phenobarbital group. The elimination constant k 2 of aminopyrine and the excretion of glucaric acid in the pre-medication period were correlated (p<O.05)o The results indicate that the tests were of diagnostic value in determination of microsomal enzyme induction by phenobarbital. Failure to observe similar changes after treatment with clemastine imply failure of induction of this activity under the experimental conditions.
The Effect of Age and Sex on Metabolism and Urinary Excretion of Antipyrine
The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 1998
Background. Drug-metabolizing capacity is generally reduced in the elderly. The purpose of this investigation was to study antipyrine clearance and metabolite excretion in old subjects of both sexes. Methods. Saliva clearance of antipyrine and the production clearances of antipyrine metabolites were studied in young and elderly volunteers of both sexes. Seventy-six elderly subjects (mean age 81 years) were compared with a group of 24 young subjects (mean age 29 years). Results. After oral administration, salivary antipyrine clearance declined with age in both males and females, whether or not this variable was corrected for weight, and antipyrine half-life was significantly prolonged in elderly groups of either sex. The percentage urinary excretion of the antipyrine metabolites (hydroxymethylantipyrine, HMA; norantipyrine, NORA; and 4-hydroxyantipyrine, OHA) was reduced at 48 h in the elderly compared to young subjects by 23%, 31%, and 10%, respectively, in males, and by 41%, 41%, and 24%, respectively, in females. The formation clearance of HMA was reduced by 47% in males and by 52% in females. NORA clearance declined by 42 and 56%, respectively, in males and females. A decrease of 30% in males and 44% in females was observed in OHA clearance. Conclusions. The findings suggest that aging leads to altered disposition of antipyrine in both males and females and that the main metabolic pathways of the compound are not different in the elderly.
Effect of antipyrine and phenobarbital on renal γ-glutamyltransferase excretion in human urine
Clinical Pharmacology and Therapeutics, 1990
Effect of antipyrine and phenobarbital on renal y-glutamyltransferase excretion in human urine Serum y-glutamyltransferase is used as a marker of hepatic enzyme induction. The kidney contains high activities of y-glutamyltransferase in the brush border membrane of the proximal tubule, from which it is released into urine. This study investigated the effect of phenobarbital and antipyrine, two inducers of hepatic monoxygenases and y-glutamyltransferase, on the urinary excretion of renal y-glutamyltransferase. Three groups (n = 6) of healthy male volunteers received 100 mg phenobarbital for 7 and 14 days and 1200 mg antipyrine for 7 days, respectively. Antipyrine and phenobarbital increased antipyrine elimination, serum y-glutamyltransferase, and the urinary excretion of renal y-glutamyltransferase, whereas urinary 13-N-acetylglucosaminidase, fl-glucuronidase, and total protein and glucose excretion were unchanged. No correlation was found between serum and urinary y-glutamyltransferase or both enzymes and antipyrine elimination Increases in antipyrine elimination were positively correlated to increases in serum, but not urinary y-glutamyltransferase. The findings suggest that antipyrine and phenobarbital increase urinary y-glutamyltransferase excretion. However, the increase in urinary y-glutamyltransferase does not reflect the magnitude of hepatic enzyme induction.
A monoamine oxidase inhibitor in human urine
Biochemical Pharmacology, 1980
Enzyme inhibitors may be useful as drugs FT. Although some endogenous enzyme inhibitors are well recognised, e.g. of dopamine B-hydroxylase [Z], their possible in tivo roles as physiological regulators of enzyme activity have been little studied. Following an earlier and as yet unconfirmed report [3] that plasma from schizophrenics with low platelet monoamine oxidase (MAO) (EC 1.4.3.4.) activity contains an MAO inhibitor not demonstrable in normal plasma, we have been able to demonstrate that normal human urine contains an inhibitor or inhibitors of both MAO A and 6, and that this inhibition cannot be accounted for by the activity of the quantitatively main urinary constituents or by a large group of known monoamine substrates or metabolites. The inhibitor was assayed by its effect on rat liver MAO. Except where specified otherwise, the test system contained 100 J,I~ of 0.1 M sodium phosphate buffer, pH 7.4, 20 ul rat liver homogenate (2.5% w/v), 20 ~1 14C-tyramine (150 yM, sp.act. 2.5 ~Ci/~~le~ and 100 ~1 of urine, or potential inhibitory substances diluted in buffer or of buffer alone. The mixture was incubated at 37'C for 30 min, the reaction stopped with 0.1 ml of 2 M citric acid and the reaction products extracted into 3 ml toluene/ethyl acetate (1:l). A similar system was used with '"C-5-hydroxytryptamine (5-HT) (sp.act. 2.5 uCi/umole) but when "'C-phenylethylamine (PEA) (sp.act. 12.5 ~C~/~mole) was used as substrate, 3 ml toluene alone was employed. Radioactive substances were obtained from the Radiochemical Centre, Amersham. Assays were carried out in duplicate, using reagents of analytical grade, from British Drug Houses (Poole, U.K.) or Sigma London Chemical Co.Ltd. (Kingston-upon-Thames. U.K.). All the human urine samples (random specimens from 14 normal subjects) tested showed varying degrees of inhibition ranging from 25-75%, with a mean of 49% f 7.1 (mean * S.D.), The degree of inhibition was similar when the pH of the urine was adjusted to pH 7.4, and whether a flocculent or clear portion of urine was tested. Human platelet (1 mg protein/ml) MAO was inhibited to a similar extent by the various samples, so that the effect does not depend on the generation of an inhibitor by rat liver. Constituent Cont. % Inhibition Constituent Cont. % Inhibition (mg/lOOml) (mg/lOOml) Urea 2000 4 Glycine 44 0
European Journal of Clinical Pharmacology, 1983
Sulphinpyrazone decreases the plasma clearance of tolbutamide and S-warfarin and increases the clearance of R-warfarin, theophylline and antipyrine. In order to determine whether sulphinpyrazone is an inducer or inhibitor or both of oxidative drug metabolism, antipyrine and its metabolites as well as 6-beta-hydroxycortisol were measured in urine before, 24h and after 23 days of chronic administration of sulphinpyrazone (4 x 200 rag/day). During chronic treatment sulphinpyrazone increased the ratio of 6-beta-hydroxycortisol to the 17-hydroxycorticosteroids by 70% (p< 0.02). The renal clearance of the main oxidative metabolites of antipyrine (4-hydroxyantipyrine, 3-hydroxymethylantipyrine and norantipyrine) were increased after sulphinpyrazone (p<0.02). Except for norantipyrine, no change in total excretion of antipyrine and its metabolites occurred after 24 h or after 23 days. It is concluded that sulphinpyrazone induces the enzymes which metabolize antipyrine and cortisol.
Accuracy of the one-sample method for determination of antipyrine clearance in elderly subjects
Journal of Pharmaceutical and Biomedical Analysis, 1996
The purpose of this study was to evaluate the validity of the one-sample abbreviated method for determination of the pharmacokinetic parameters of antipyrine in the elderly. Antipyrine pharmacokinetics were studied in 15 elderly women (mean age 86 years). Antipyrine (1 g) was administered orally and pharmacokinetic parameters were determined by the one-sample (24 h) and multiple-sample (3, 6, 9, 12 and 24 h) methods. Mean antipyrine clearance for the one-sample study (19.72 + 1.51) was almost identical to that obtained with the multiple-sample approach (20.73 + 1.57), and the two methods were very well correlated (r = 0.989). Relative standard deviations between individual clearances values for multiple-sample vs. one-sample studies averaged 1.6%. Values of elimination half-life were likewise very similar for the abbreviated (17.41 + 1.21) and complete (17.99 + 1.09) methods, with a significant correlation (r = 0.857). Although values were underestimated by 10%, in the one-sample approach, no difference in the volume of distribution with the multiple-sample study was observed. When the unbiased volume of distribution value was determined from the total elimination curve against time, the influence of biased volume of distribution resulted in a 5.1% deviation in antipyrine clearance in the one sample method. The findings indicate that antipyrine pharmacokinetic parameters can be estimated with reasonable precision and accuracy in the elderly using a simplified one-sample procedure. and is extensively metabolized by the cytochrome P-450 liver enzymes. Antipyrine shows a negligible protein binding and its elimination is not limited by liver blood flow, which declines with age. Changes in hepatic oxidative capacity contribute to altered responses to drugs in the elderly, and specific information concerning hepatic function can be obtained by estimation of antipyrine kinetic parameters [1]. In a number of studies 0731-7085/96/$15.00
Assessment of antipyrine kinetics from saliva or plasma: influence of age
Journal of Pharmaceutical and Biomedical Analysis, 1995
The purpose of this study was to investigate whether antipyrlne estimation in saliva provides wdid information on plasma antipyrine clearance (APc0 and can be useful as an index of changes in drug metabolism with age. Antipyrine kinetics was studied in 93 elderly (mean age 82 years) and 23 young (mean age 29 years) volunteers. Plasma antipyrine half-life (APh,2) increased and plasma APc~ declined with age. No significant difference between plasma-and saliva-derived parameters was found in either young or old subjects. However, the saliva/plasma ACcl ratio tended to increase with age. A highly significant correlation between saliva and plasma APcl or APt~/2 was found in young subjects. Values were less closely related in the elderly and the slope of the saliva/plasma APc~ relationship was significantly different in both groups of subjects. Residual variance was higher in the regressions corresponding to the elderly. The findings in the study indicate that the relationship between saliva and plasma kinetics in young subjects becomes less reproducible with age. Kevwords': Age: Antipyrine: Oxidative metabolism: Plasma: Saliva * Corresponding author. Tel: 34 87 291258. Fax: 34 87 291267. 0731-7085/95/$09.50 ;c::, 1995 Elsevier Science B.V. All rights SS'DI (1731-7(185(95)01 531-0
Antipyrine elimination and hepatic microsomal enzyme activity in patients with liver disease
Clinical pharmacology and therapeutics, 1990
Induction of hepatic monooxygenases reflected by 7-ethoxycoumarin O-deethylase has been proposed to be associated with the initiation of liver damage. This study investigated a possible correlation between 7-ethoxycoumarin O-deethylase, reduced nicotinamide adenine dinucleotide phosphate cytochrome c reductase and benzypyrene hydroxylase activity in liver biopsy specimens of 31 patients with liver disease and antipyrine elimination, an in vivo parameter of hepatic monooxygenase activity. No correlation was found between the enzyme activities and antipyrine clearance or half-life. When microsomal enzyme activities were compared with the formation rate of 4-hydroxyantipyrine, 3-methylhydroxyantipyrine, and norantipyrine, a correlation was found only between benzo[alpha]pyrene hydroxylase and 3-methylhydroxyantipyrine (r = 0.89; p less than 0.0005). There was also a correlation between 7-ethoxycoumarin O-deethylase and reduced nicotinamide adenine dinucleotide phosphate cytochrome c re...
European Journal of Drug Metabolism and Pharmacokinetics, 1979
The administration to the rat of the inhibitors of microsomal mixed function oxidases, SKF S2S-A and Oxine-S-sulphonic acid (OSA) caused a significant decrease of the hepatic aminopyrine N-demethylase activity, as well as an increase in the plasma levels and antipyretic activity of orally administered aminopyrine. The plasma concentrations of the aminopyrine metabolite 4-aminoantipyrine were reduced in SKF S2S-A treated animals while they were slightly increased in those pretreated with OSA. These findings suggest that the in vivo changes of aminopyrine disposition and activity brought about by SKF S2S-A were the result of an inhibited hepatic drug metabolism, while the effects produced by OSA were due to a more rapid intestinal absorption of aminopyrine.