Relationship between Plasma Antipyrine Half-Lives and Hepatic Microsomal Drug Metabolism in Dogs

Vesell, E S; Lee, C.J.; Passananti, G. Thomas; Shively, Carol A.

doi:10.1159/000136453

Cited by 53 publications

(14 citation statements)

References 5 publications

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“…Thus it is postulated that variance in antipyrine clearance is composed of variance in drug metabolizing enzyme concentration and activity plus variance in mass of functional hepatic parenchyma. This hypothesis would be consistent with the finding that in experimental models antipyrine biotransformation in vivo does correlate with that in vitro in animals selected for similarity in weight (Statland, Astrup, Black and Oscholm, 1973;Vesell, Lee, Passaranti & Shively, 1973). Similarity in liver size might explain the smaller intrapair variance in antipyrine half-life seen in identical twins as compared to fraternal twins (Vesell & Page, 1969).…”

Section: Discussionsupporting

confidence: 83%

The relationship between liver volume, antipyrine clearance and indocyanine green clearance before and after phenobarbitone administration in man.

Roberts¹,

Jackson²,

Halliwell³

et al. 1976

Brit J Clinical Pharma

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General Hospital, Bristol I Liver volume and the clearances of antipyrine and indocyanine green have been measured before and after administration of phenobarbitone (180 mg/day) for 3 weeks to ten healthy subjects. 2 The measurement of liver volume by an ultrasound scanning technique yielded reproducible results which were consistent with predictions of liver size by allometric methods. 3 Before phenobarbitone, antipyrine clearance correlated with liver volume, but there was no correlation between indocyanine green clearance and liver volume. 4 Phenobarbitone administration increased the clearance of antipyrine significantly by 90 ± 14% but there was no significant change in indocyanine green clearance or liver volume. 5 After phenobarbitone the correlation between antipyrine clearance and liver volume persisted. There was no correlation between indocyanine green clearance and liver volume. 6 These results suggest that in non-medicated subjects some of the difference in antipyrine clearance is due to difference in functional hepatic parenchymal mass and that phenobarbitone increases the drug metabolising capacity per unit of hepatic mass but not total liver size.

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Section: Discussionsupporting

confidence: 83%

The relationship between liver volume, antipyrine clearance and indocyanine green clearance before and after phenobarbitone administration in man.

Roberts¹,

Jackson²,

Halliwell³

et al. 1976

Brit J Clinical Pharma

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“…In atro phied livers of PCS rats, reductions in the amounts of cytochrome P-450 by 40 and 50% have been observed [18,28], This means that the cumulative decrease in he patic function in this study, as based on the cited literature and the liver weight data from table I, is approximately 60%. This value agrees closely with the reduction in AP clear ance; AP clearance reflects hepatic enzyme activity [29,30], HB with an extraction ratio of about 0.65 is an intermediately 'high-clearance' drug. Provided HB is given by the oral route of administration, mean blood clearance as de termined by D/AUC reflects enzyme activity in the liver [31].…”

Section: Discussionsupporting

confidence: 76%

Correlation between the in vivo Metabolism of Hexobarbital and Antipyrine in Rats with a Portacaval Shunt

et al. 1984

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To investigate how hepatic malfunction affects the disposition of hexobarbital (HB), an intermediate ‘high-clearance’ compound, and antipyrine (AP), a low-clearance compound, as well as the correlation between the rates of elimination of these drugs, their pharmacokinetics, were studied in control rats (n = 8) and in rats with a portacaval shunt (PCS; n = 9). Blood concentrations of parent drugs were measured, and urinary excretion of the following metabolites was determined: 3-hydroxymethylantipyrine (HMA), 4-hydroxyantipyrine and norantipyrine as primary metabolites of AP, and 3’-hydroxyhexobarbital (OH-HB) and 3’-ketohexobarbital (K-HB) as primary metabolites of HB.Blood elimination half-lives of AP and HB were more than four times longer in PCS rats than in control rats, increasing from 63.7 ± 3.9 to 291 ± 66 min, and from 20.1 ± 1.8 to 84.2 ± 7.6 min, respectively. Intrinsic clearance of HB (CL_{int, HB}) was 167 ± 19 ml/min/kg in controls and 27 ± 4 ml/min/kg in PCS rats (CLp_int, _HB). Intrinsic clearance of AP (CL_Mnt, ap) in control rats was 15.1 ± 0.7 ml/min/kg and 5.9 ± 0.7 ml/min/kg in PCS rats (CL_{pcs, AP}). PCS reduced clearance for production of metabolites (CL_Mn) of AP by 50%, but CL_Mn of HB metabolites was decreased by more than 80%. The CL_{int, AP}, CL_int,HB, CL_pcs,HB, CL_pcs,AP, and CL_Mn data were correlated. Total clearance correlated better in PCS rats than in control rats: r = 0.77 versus r = 0.10, respectively, thus suggesting a decrease in substrate selectivity under pathological conditions. CL_OH-HB+K-HB, reflecting the major metabolic pathway of HB, correlated most closely with CL_HMA in PCS (r = 0.91). Therefore, the underlying metabolic conversions of HB and AP may be mediated by the same or very similar forms of cytochrome P-450. Our results suggest that the predictive value of the model substrate approach is valid under pathological conditions.

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“…Results of these studies add a dimension to the application of the rate of disappearance in vivo or metabolic half-life for reflecting hepatic drug metabolism which was reported by Statland et al (28) and Vesell et al (30). Since positive correlations from regression analyses between antipyrine plasma half-life in the rabbit or dog and hepatic microsomal anti pyrine and aniline hydroxylase and ethylmorphine N-demethylase activities were noted, their findings indicate that the plasma anti-pyrine half-life reflects the hepatic microsomal metabolism of several drug substrates chemi cally unrelated to antipyrine.…”

Section: Discussionmentioning

confidence: 83%

Correlation of Phenobarbital- and SKF 525-A-Induced Modification of Pentobarbital Hypnosis with Alteration of in vivo and in vitro Pentobarbital Metabolism in the Rat

Means¹,

Schnell²,

Miya³

et al. 1978

Pharmacology

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Studies were undertaken to assess the ability of various in vitro and in vivo pentobarbital-metabolizing systems to reflect modifications in pentobarbital response following treatment with either phenobarbital or SKF 525-A. Of the in vitro systems studied, the hepatic 10,000 g supernatant and washed microsome fractions and liver slices reflected varying degrees of phenobarbital-induced stimulation of pentobarbital metabolism. Significant SKF 525-A-induced inhibition of pentobarbital metabolism was observed in the hepatic microsome fraction, liver slices, and isolated perfused liver. Plasma level decline of pentobarbital, however, was identified as the measure of pentobarbital metabolism which best reflects both phenobarbital- and SKF 525–A-induced modification of the duration of pentobarbital response. In correlating the in vitro systems with the in vivo systems of pentobarbital metabolism, both the hepatic 10,000 g supernatant and washed microsome fractions reflected phenobarbital-induced alteration of in vivo pentobarbital metabolism as determined by plasma level decline. None of the in vitro metabolism systems employed adequately reflected modification of the in vivo metabolism of the barbiturate following SKF 525-A treatment. These studies indicate that major differences exist in the sensitivity and responsiveness of in vitro hepatic and in vivo systems in their capacity to reflect modification of pentobarbital response and metabolism following phenobarbital and SKF 525-A treatment. Furthermore, the plasma level decline of a lipid-soluble drug provides the best index of hepatic drug metabolism which reflects modification of drug response following phenobarbital or SKF 525-A pretreatment.

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Relationship between Plasma Antipyrine Half-Lives and Hepatic Microsomal Drug Metabolism in Dogs

Cited by 53 publications

References 5 publications

The relationship between liver volume, antipyrine clearance and indocyanine green clearance before and after phenobarbitone administration in man.

The relationship between liver volume, antipyrine clearance and indocyanine green clearance before and after phenobarbitone administration in man.

Correlation between the in vivo Metabolism of Hexobarbital and Antipyrine in Rats with a Portacaval Shunt

Correlation of Phenobarbital- and SKF 525-A-Induced Modification of Pentobarbital Hypnosis with Alteration of in vivo and in vitro Pentobarbital Metabolism in the Rat

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