Monogenic control of variations in antipyrine metabolite formation. New polymorphism of hepatic drug oxidation.

Penno, Margaret B.; Vesell, Elliot S.

doi:10.1172/jci110924

Cited by 60 publications

(26 citation statements)

References 33 publications

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“…They were carefully selected to be under near basal environmental conditions so that their rate of theophylline metabolism would be neither markedly induced nor inhibited. 15 of the 27 family members and several twins and unrelated subjects had previously participated in the AP studies performed in this laboratory (12,16). No subject had a history of serious illness or drug allergy, consumed any medications or ethanol regularly, smoked tobacco, or was chronically exposed to inducing or inhibiting chemicals.…”

Section: Methodsmentioning

confidence: 99%

“…Evidence from other laboratories had indicated a positive correlation within subjects between rates of theophylline and AP metabolism (17)(18)(19). Therefore, only the most informative families from our AP study (12) were used, since the present study attempted to determine whether one genetic locus might control a single cytochrome P-450 isozyme that regulates both AP and theophylline metabolism. 79 unrelated individuals were deemed sufficient to uncover a commonly occurring polymorphism, i.e., one in which q > 0.1.…”

Section: Methodsmentioning

confidence: 99%

“…In addition to providing blood, three subjects collected saliva samples, which were stimulated by chewing parafilm, at 4,8,12,16,20,24,28,32, and 36 h after drug administration. These three subjects did not take theophylline again.…”

Section: Methodsmentioning

confidence: 99%

“…This approach helped to elucidate several pharmacogenetic conditions, including atypical plasma cholinesterase, the acetylation polymorphism, glucose-6-phosphate dehydrogenase deficiency, and the polymorphic oxidations of debrisoquine (10), mephenytoin (1 1), and AP (12).…”

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confidence: 99%

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Polymorphism of theophylline metabolism in man.

Miller¹,

Slusher²,

Vesell³

1985

J. Clin. Invest.

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To determine whether genetic mechanisms control large interindividual variations in theophylline elimination in normal uninduced human subjects, and, if so, to test the possibility that these genetic factors are transmitted as a simple Mendelian trait, theophylline was administered to 79 unrelated adults, six sets of monozygotic twins, six sets of dizygotic twins, and six two-generation families. Thereafter, in urine collected from each subject at regular intervals for 48 h, concentrations of theophylline and its three principal metabolites were measured and rate constants of formation of these metabolites calculated.The twin study, designed to determine the relative contributions of genetic and environmental factors to large interindividual variation in theophylline elimination, revealed predominantly genetic control. Values for this genetic component, designated heritability (HI2), of interindividual variation in rate constants of metabolite formation were 0.61, 0.84, and 0.95 for 3-methylxanthine, 1-methyluric acid, and 1,3-dimethyluric acid, respectively. HI2 for the overall theophylline elimination rate constant (kei) was lower (0.34).In the 79 unrelated adults, each distribution curve for rate constants of formation of each theophylline metabolite appeared to be trimodal. By contrast, the distribution curve for the overall theophylline elimination rate constant appeared to be either unimodal or bimodal. The extent of interindividual variation was fourfold for theophylline kei and 6-8-fold for the three principal metabolites. High correlations among the three rate constants in individual subjects suggested their regulation by a single shared factor.In six families carefully selected to be under near basal environmental conditions so that hepatic theophylline metabolism of each family member would be neither markedly induced nor inhibited, phenotypes for theophylline metabolite rate constants were assigned. This assignment of phenotype was made by the position of each family member's rate constant on the three distribution curves that were generated from the 79 unrelated subjects. In each family, pedigree analysis of the three phenotypes for each rate constant was consistent with their control by two alleles at a single genetic locus and with autosomal codominant transmission. Frequencies of the two alleles at each genetic locus controlling rate constants of formation of theophylline metabolites were similar (p = 0.49, 0.53, and 0.52). In the three families studied with antipyrine (AP) as well as with theophylline, AP

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Polymorphism of theophylline metabolism in man.

Miller¹,

Slusher²,

Vesell³

1985

J. Clin. Invest.

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“…While evaluating the present results. one must also consider that the MFO system activity is genetically conditioned and it shows large "species difference" (Penno and Vesell 1983;Kalow 1987;Loft 1990;Pantuck etal. 1991).…”

Section: Resultsmentioning

confidence: 99%

Hepatic Biotransformation Rate in Calves Fed Diets with Proteinor Carbohydrate Supplements

Janus¹,

Muszczynski²,

Skrzypczak³

1996

Acta Vet. Brno

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The purpose of the study was to evaluate (on the basis of pharmacokinetics of antipyrine) the hepatic biotransformation rate in calves in neonatal period. The calves received supplementary casein or glucose in their food ration. It was found that an increased protein content in the diet significantly increased the hepatic biotransformation rate as indirectly indicated by the monooxygenase activity linked to cytochrome P450. Increased carbohydrate content in the diet produced an opposite effect upon the activity of the system. From these results it can also be concluded that a high-protein diet would increase whereas a high-carbohydrate diet would decrease the metabolism of other of drugs in calves, provided they would undergo the same biotransformation process as antipyrine does. AllIipyrine. neonatal period. casein. glucose. liver. MFO system

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Chemical Synthesis of Phase‐I‐ and Phase‐II‐Metabolites of Antipyrine

Krohn

Stenns

1989

Archiv der Pharmazie

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The chemical synthesis of the hydroxylated phase-I-metabolites 9, 11, and 12 is effected by Triton B catalysed saponification of the bromides 7 and 8Chemische Synthese der Phase-I-und Phase-II-Metaboliten des Antipyrim and boron tribromide mediated ether cleavage of 6 and 10 to 11 and 12. The chelated enol was coupled with the bromosugar 13 to afford the glucuronide 14 that was saponified to the phase-11-metabolite 15.Die hydroxylierten Phase-I-Metaboliten 9, 11 und 12 werden dwch Triton B-katalysierte Verseifung der Bromide 7 und 8 und Etherspaltung von 6 und 10 mit BoItribromid zu 11 und 12 bereitet. Das chelierte Enol 9 wird mit dem Bromzucker 13 zum Glucuronid 14 gekoppelt und zum Phase-II-Metaboliten 15 verseift.Antipyrine ( 1 -phenyl-2,3-dimethylpyrazoline-5-one, phenazone, 5 ) the classical pyrazolone analgesic, has gained wide acceptance during the last two decades as a model substance in clinical as well as in biochemical pharmacological research'). Using this model two different approaches have evolved to test the drug hydroxylation activity in vivo:1. direct determination of the elimination kinetics of the unchanged antipyrine (drug) from the blood, plasma or saliva '-' ), 2. assay urinary profiles of antipyrine metabolites either of phase-I '-*) or phase-I1 ' ).In fact, determination of the urinary pattern of hydroxylated metabolites has become a promising means for the assessment and the analysis in vivo of the various activities of cytochrome-P450 isoenzymes involvedThe hydroxylation pattern of antipyrine in humans as well as in animals is sufficiently complex to form a series of primary hydroxylated metabolites (4-hydroxy-antipyrine (9), 2-methyl-3-hydroxymethyl-1 -phenyl-3-pyrazoline-5-one, ("3-hydroxymethyl-atipyrine"), 4'-hydroxy-antipyrine (11) and some secondary hydroxylated metabolites (4,4'-dihydroxy-antipyrine (12) the assay of which can now be handled satisfactorily by different analytical 1 9 ) .However, as a consequence of its widespread use in the field of pharmacology, toxicology, and pharmacokinetics etc., there is an actual need for some of these phase-I and phase-I1 metabolites as standards for use in assays. As 4-hydroxy-antipyrine and norantipyrine are commercially available and a satisfactory synthesis for 3-hydroxymethyl-antipyrine has been described * ' ) we developed a productive synthesis for 4'-hydroxy-antipyrine (11) and 4'-dihydroxyantipyrine (12) as well as the glucuronosylated phase-11-metabolite (4-hydroxy-antipyrine glucuronide (15). Results and DiscussionThe direct chemical hydroxylation of antipyrine (5) by the method of Brody et al.") gives a complex mixture in low yield that is difficult to separate (BuJ?mnn221). We decided to introduce the hydroxy groups at C-4 and C-4' in a stepwise and clearly defined manner. Our first goal was the preparation of 4'-hydroxy-antipyrine (11) via methyl ether cleavage of 6. An adaptation of the original condensation 23) of acetoacetic ethyl ester with 4-methoxyphenylhydrazine was used to synthesize the starting material 2 "! In add...

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Monogenic control of variations in antipyrine metabolite formation. New polymorphism of hepatic drug oxidation.

Cited by 60 publications

References 33 publications

Polymorphism of theophylline metabolism in man.

Polymorphism of theophylline metabolism in man.

Hepatic Biotransformation Rate in Calves Fed Diets with Proteinor Carbohydrate Supplements

Chemical Synthesis of Phase‐I‐ and Phase‐II‐Metabolites of Antipyrine

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