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PubMed1987

Aminopyrine N-demethylation by rats with liver cirrhosis. Evidence for the intact cell hypothesis. A morphometric-functional study.

The intact cell hypothesis states that a reduced number of intrinsically normal hepatocytes, together with hemodynamic alterations, explains decreased drug metabolism in cirrhosis. We explored this hypothesis by comparing results of the aminopyrine breath test with in vitro measurements of aminopyrine N-demethylation and morphometrically determined liver cell volume in a rat model of cirrhosis. Aminopyrine N-demethylation in vivo (ABT-k) was 0.98 +/- 0.10/h (mean +/- SD) in controls. The cirrhotic rats were separated into those with normal (NCR) and those with abnormal ABT-k (PCR). Microsomal aminopyrine N-demethylase averaged 2.08 +/- 0.77 and 2.09 +/- 0.54 mumol/min in controls and NCRs, respectively; it was reduced to 1.00 +/- 0.81 mumol/min (p less than 0.02) in PCRs. Morphometrically determined hepatocellular volume was 18.8 +/- 2.8, 17.1 +/- 1.9, and 11.6 +/- 6.1 ml in controls, NCRs, and PCRs, respectively, PCRs being lower than controls (p less than 0.01) and NCRs (p less than 0.05). When N-demethylase and cytochrome P450 were related to hepatocellular volume (in milliliters), no significant difference between the three groups was apparent. We conclude that reduced aminopyrine N-demethylation in progressed cirrhosis is mainly due to a loss of liver cell volume. The function per liver cell volume remains constant, however, thus favoring the intact cell hypothesis for the handling of slowly metabolized compounds such as aminopyrine.

Aminopyrine↗
PubMed1980

Aminopyrine N-demethylation: a prognostic test of liver function in patients with alcoholic liver disease.

To determine whether results of the aminopyrine breath test, an indirect measurement of functional hepatic microsomal mass, can be correlated with mortality and changes in clinical status and liver function, 51 hospitalized patients who had alcoholic hepatitis were studied prospectively for 3 wk. The aminopyrine breath test was performed weekly, and the results were compared with clinical features of liver disease and SGOT, SGPT, bilirubin, albumin, and prothrombin time. Only an aminopyrine breath test of > 1% of administered dose of 14C as 14CO2 correlated with 3-week survival (P = 0.0075). Only an increase of more than 100% in the aminopyrine breath test was associated with clinical improvement (P = 0.0036). For the 21 patients who had histologic confirmation of alcoholic liver disease, the aminopyrine breath test also correlated best with the degree of histologic severity. In this group of patients with alcoholic hepatitis the aminopyrine breath test predicted short-term survival, clinical improvement, and histologic severity more reliably than conventional liver function tests.

Adult↗
PubMed1975

Studies on the disposition of antipyrine, aminopyrine, and phenacetin using plasma, saliva, and urine.

In normal male subjects, the half-lives of antipyrine, aminopyrine, or phenacetin were not significantly different from the half-lives of each drug in saliva. Apparent volumes of distribution (aVd) in plasma and saliva differed by the extent to which each drug has been reported to bind to plasma proteins. Thus, the aVd of antipyrine in plasma and saliva was similar; there were significant differences in aVd for aminopyrine; even greater differences were observed for penacetin. The expression (see article) equals the fraction of the drug bound to plasma proteins. Rates of appearance in the urine of metabolites of antipyrine and aminopyrine were measured. General equations were used to show the relationship between half-life for elimination of the parent drug from the body and rate of excretion of metabolites. There were significant correlations between the half-life for elimination of antipyrine from the body and the half-life for production of 4-OH antipyrine (r equal 0.90), as well as between the plasma half-life of aminopyrine and the half-life of 4-aminoantipyrine (r equal 0.95). No significant correlation was observed in the same individual between the plasma half-lives of antipyrine and phenacetin (r equal 0.05, p greater than 0.05), of aminopyrine and phenacetin (r equal 0.11, p greater than 0.05), or of antipyrine and aminopyrine (r equal 0.50, p greater than 0.05).

Acetylation↗
PubMed1983

Direct preparation of solid particulates of aminopyrine-barbital complex (pyrabital) from droplets by a spray-drying technique.

Aqueous slurries of aminopyrine and barbital (molecular ratio 2:1) containing various excipients such as colloidal silica, synthetic aluminum silicate, montmorillonite clay, corn starch, microcrystalline cellulose, hydroxypropylcellulose, methylcellulose, gelatin, and chitosan were spray-dried by a centrifugal wheel atomizer with various rotation speeds (10,000-40,000 rpm) at various temperatures (85-145 +/- 5 degrees). The spray-dried products were a mixture of aminopyrine-barbital complex (molecular ratio 1:1), aminopyrine, and the excipient used. The flowability and the packing property of the products were improved by compounding colloidal silica into the formulation used for spray-drying. The products with montmorillonite clay, chitosan, and a corn starch-colloidal silica mixture were compressed directly into tablets. It was found that aminopyrine in the products was oxidized during spray-drying. The oxidation products were assumed to be a trace mixture of 5-oxo-2-methyl-4-dimethylamino-1-phenyl-3-pyrazoline carboxyaldehyde and miscellaneous oxidation products. Montmorillonite clay compounded in the formulation considerably prevented the oxidation of aminopyrine during spray-drying. The present study proposes an improved method for the preparation of solid particulates of aminopyrine-barbital complex for tableting, which combines the synthesis, drying, and agglomeration processes into a single process.

Aerosols↗
PubMed1987

Studies on the metabolism of aminopyrine, antipyrine and theophylline using monoclonal antibodies to cytochrome P-450 isozymes purified from rat liver.

We investigated the role played by monoclonal antibody defined classes of cytochrome P-450 in the metabolism of antipyrine, aminopyrine and theophylline. Two enzyme inhibitory monoclonal antibodies (MAb 1-7-1 and MAb 2-66-3) raised to two forms of cytochrome P-450 were used. Microsomes were prepared from the livers of untreated, 3-methylcholanthrene (MC)-treated, and phenobarbital (PB)-treated male Wistar rats. Addition of either monoclonal antibody to hepatic microsomes from untreated rats had a negligible effect on the metabolism of aminopyrine, antipyrine or theophylline. These results indicate that the constitutive enzymes responsible for metabolism of these three drugs differ from the MAb inhibitable enzymes responsible for transformation of these drugs in induced microsomes. In microsomes from MC- and PB-treated rats, however, the two MAbs differentially inhibited individual pathways. For example, at 20 mM aminopyrine, as much as 55% of 4-amino-antipyrine (4-AA) formation arose from the family of cytochrome P-450 isozymes that were not inhibited for 4-AA formation at 4 mM aminopyrine and 4-methylaminoantipyrine (4-MAA) formation at either concentration. Thus, the enzyme that functions at 20 mM aminopyrine in 4-MAA formation differs from that which functions at 4 mM aminopyrine in the formation of 4-AA or 4-MAA. Addition of MAbs to induced microsomes revealed at least four isozymes with overlapping specificities involved in antipyrine and theophylline metabolism. Each MAb-inhibitable pathway and the isozymes associated with it were classified into one of three epitope families: those pathways inhibited by both MAbs, those inhibited only by the MAb raised against PB-inducible P-450 isozymes, and those inhibited only by the MAb raised against 3-MC-inducible P-450 isozymes. A fourth group of pathways consisted of those unaffected by addition of either monoclonal antibody. Analysis of metabolism with these two MAbs suggests more extensive heterogeneity of the isozymes that biotransform these drugs than previously recognized.

Aminopyrine↗
PubMed1982

Perturbation of hepatic glutathione level and glutathione-related enzyme activities by repeated administration of aminopyrine in rats.

The influence of repeated administration of aminopyrine on the tissue glutathione level and related enzyme activities was investigated in rats. Reduced glutathione level in the liver was not changed after 5 days of treatment but a significant increase was seen after 15 days of aminopyrine treatment. Oxidized glutathione level was unaltered throughout the experiment. Repeated administration of aminopyrine for 5 days caused a marked increase in gamma-glutamyl transpeptidase activities in liver whole homogenates as well as in the nuclear fraction, but not in liver microsomes. These results suggest that gamma-glutamyl transpeptidase located in plasma membrane may be induced by repeated administration of aminopyrine for 5 days. The activities of cytosolic glutathione peroxidase, which modulates glutathione level, were also significantly increased by aminopyrine treatment. Under the same conditions, glutathione peroxidase activity with H2O2 as a substrate was unaltered, while a time-dependent increase in the activity was found when cumene hydroperoxide was used as a substrate, even after a single administration of aminopyrine. The intracellular cysteine level was increased accompanying the increased gamma-glutamyl transpeptidase activities. Therefore, induced gamma-glutamyl transpeptidase may play a role in the reclamation of extracellular oxidized glutathione.

Administration, Oral↗
PubMed1993

Gastrin action on aminopyrine accumulation in isolated pig parietal cells requires cAMP.

The mechanism of action of gastrin on pig parietal cells was investigated. The aminopyrine accumulation technique was used to estimate acid production in gastric mucosal cells, containing 10-20% parietal cells, and in enriched parietal cells, containing 65-95% parietal cells. The gastrin analogue pentagastrin stimulated aminopyrine accumulation in a dose-dependent fashion irrespective of the proportion of non-parietal cells present. The apparent EC50 for pentagastrin was 5 nM and the maximally effective concentration was 100 nM. The histamine H2-receptor antagonist ranitidine did not affect the action of pentagastrin. The stimulatory effects of various doses of histamine on aminopyrine accumulation in highly enriched parietal cells were potentiated by the inclusion of 100 nM pentagastrin in the incubation medium. In another series of experiments using mucosal cells, the action of effective doses of pentagastrin were potentiated by the phosphodiesterase inhibitor isobutylmethyl xanthine (IBMX), which alone elicited an aminopyrine accumulation equal to 50% of that obtained by 100 microM histamine. When ranitidine (100 microM) was included, the action of IBMX was almost completely abolished. However, the dose-response curve for pentagastrin in the presence of ranitidine plus IBMX was similar to that obtained in the absence of IBMX. Dibutyryl-cAMP (DBcAMP, 1 mM) in the presence of ranitidine (100 microM) also potentiated the action of all effective doses of pentagastrin on mucosal cells. The protein kinase A inhibitor Rp-cAMPS, present at 500 microM in the incubation medium, significantly reduced the action of each effective concentration of pentagastrin on aminopyrine accumulation in enriched parietal cells. These results in pig parietal cells were interpreted as indicative of: (i) an action of gastrin exerted directly on the parietal cells; (ii) elevation of intracellular cAMP having a permissive role in the action of gastrin on aminopyrine accumulation.

1-Methyl-3-isobutylxanthine↗
PubMed1985

Metabolism and gastric acid secretion. Substrate-dependency of aminopyrine accumulation in isolated rat parietal cells.

The substrate-dependency of gastric acid secretion was investigated in isolated rat parietal cells by using the accumulation of the weak base aminopyrine as an index of acid secretion. Exogenous substrates enhanced accumulation of aminopyrine in rat parietal cells stimulated by secretagogues, and this effect was probably directly related to the provision of energy for acid secretion. At physiological concentrations, certain of the substrates (glucose, oleate, lactate, D-3-hydroxybutyrate, L-isoleucine, L-valine and acetoacetate) could support acid secretion, with glucose being the most effective. L-Leucine and acetate were only effective stimulators of parietal-cell aminopyrine accumulation at high concentrations (5mM). L-Glutamine was unable to stimulate aminopyrine accumulation even at high concentrations, and glutaminase activity in parietal cells was estimated to be low by comparison with small-intestinal epithelial cells. Variation in the concentrations of D-3-hydroxybutyrate and L-isoleucine, but not of glucose, within the physiological range affected their ability to support aminopyrine accumulation. The presence of 5 mM-L-isoleucine, 5 mM-lactate and combinations of certain substrates at physiological concentrations produced aminopyrine accumulation in stimulated parietal cells that was greater than that obtained in cells incubated with 5 mM-glucose alone. In conclusion, fulfillment of the metabolic requirements of the acid-secreting parietal cell under physiological circumstances requires a combination of substrates, and integration of the results with previous data [Anderson & Hanson (1983) Biochem. J. 210, 451-455; 212, 875-879] suggests that after overnight starvation in vivo metabolism of glucose, D-3-hydroxybutyrate and L-isoleucine may be of particular importance.

Amino Acids↗
PubMed1978

Hepatic metabolism of aminopyrine in patients with chronic renal failure.

1. To evaluate potential alterations in hepatic metabolism of drugs occurring in patients with renal insufficiency the fate of aminopyrine was studied in 17 patients with chronic renal failure and in 27 normal subjects. 2. Although patients with chronic renal failure exhibited large variations, their aminopyrine plasma disappearance times (mean 0.62 +/- SD 0.24 h-1) were significantly higher than those found in normal subjects (0.30 +/- 0.07 h-1, P less than 0.002). 3. 14CO2 derived from [dimethylamine-14C]aminopyrine disappeared from breath more rapidly in patients with chronic renal failure and a history of analgesic abuse (0.40 +/- 0.04 h-1) than in control subjects (0.22 +/- 0.03 h-1, P less than 0.01) and in other patients with chronic renal failure (0.24 +/- 0.04 h-1). 4. Dialysis treatment and serum creatinine concentrations were not correlated with the rates of aminopyrine metabolism. Two additional patients, however, with combined renal and hepatic disease, exhibited markedly slowed rates of aminopyrine demethylation. 5. Although chronic renal failure by itself might not alter microsomal drug metabolism it is concluded that, in patients with a history of abuse of phenacetin-containing analgesics, marked acceleration in aminopyrine N-demethylation may be observed.

Adult↗
PubMed1992

[Effects of analgesic-antipyretics on the spinal reflex potentials in cats: an analysis of the excitatory action of aminopyrine].

The effects of some analgesic-antipyretics on the spinal reflex potentials were studied in spinal cats. Aminopyrine at 25-100 mg/kg, i.v. produced a marked increase in mono- and poly-synaptic reflex potentials (MSR and PSR), and a decrease in dorsal root reflex potentials (DRR) in a dose-dependent manner. The amplitude of DRR decreased by aminopyrine was reversed by diazepam at 0.2 mg/kg, i.v.; however, the increased amplitudes of MSR and PSR were not affected by diazepam. Pretreatment of semicarbazide at 200 mg/kg, i.v. did not influence the increasing effect of aminopyrine on MSR and PSR. DL-5-Hydroxytryptophan produced facilitation of the MSR and PSR. In DL-5-hydroxytryptophan-treated cats, the amplitude of MSR was further increased by aminopyrine. Methysergide at 1 mg/kg, i.v. antagonized this increasing effect of aminopyrine on MSR and PSR. These observations suggest that the excitatory action of aminopyrine may be partly related to 5-hydroxytryptamine and not connected to the GABAergic mechanism. Other pyrazolone derivatives were also studied. Isopropylantipyrine at 50 mg/kg, i.v. produced increases in MSR and PSR. Intravenous sulpyrine at 500 mg/kg, antipyrine at 50 mg/kg or 4-aminoantipyrine at 50 mg/kg did not affect the reflex potentials. The non-pyrazolones, acetaminophen and indomethacin, did not increase the MSR and PSR. These results suggest that the N-dimethyl or isopropyl residue at the 4 position of the pyrazolone structure plays an important role in the excitatory action of analgesic-antipyretics in cat spinal cord.

5-Hydroxytryptophan↗
PubMed1989

Different modes of inhibition of rat gastric mucosal 6-keto-PGF1 alpha production by indomethacin, aspirin and aminopyrine.

The actions of aminopyrine on rat gastric mucosal cyclooxygenase activity in vitro were investigated and compared with those of the cyclooxygenase inhibitors indomethacin and aspirin. Aminopyrine is a phenyl-pyrazolone derivative with potent analgesic and antipyretic properties, but is weakly ulcerogenic, while indomethacin and aspirin are known to cause considerable ulcerogenesis. Aminopyrine was less potent in its ability to inhibit cyclooxygenase activity. The inhibition by all three drugs decreased with an increase in the substrate concentration. Pre-incubation with the enzymes greatly increased the inhibitory action of indomethacin and aspirin, but only slightly increased that of aminopyrine. The inhibitory action of aminopyrine was reversible, whereas those of indomethacin and aspirin were irreversible. These findings are discussed in relation to the low incidence of gastrointestinal irritation caused by aminopyrine.

6-Ketoprostaglandin F1 alpha↗
PubMed1993

Effects of H1-receptor antagonists on 14C-aminopyrine accumulated in histamine-stimulated rabbit gastric glands.

After stimulation of gastric acid production there is a considerable delay before the acid starts to appear in the gastric lumen. The present study was carried out on isolated gastric glands to test the hypothesis that there may be a mechanism in the parietal cell that contributes to this delay by preventing emptying of the secretory canaliculi. Glands were incubated with 14C-aminopyrine and stimulated with histamine. After accumulation of 14C-aminopyrine various concentrations of H1-receptor antagonists were added. Clemastine, promethazine, and hydroxyzine effectively and cetirizine and tripelennamine less effectively decreased the accumulated 14C-aminopyrine content in a dose-dependent manner without significantly reducing the oxygen consumption. The H1-receptor antagonists influenced the 14C-aminopyrine content in another manner than H2-receptor antagonists. No effects were obtained by atropine or lidocaine, indicating that the elimination of 14C-aminopyrine is not an anticholinergic effect or due to membrane effects as exerted by local anesthetics. Stimulation of glands by further addition of histamine did not significantly stimulate the uptake of 14C-aminopyrine in the glands, whereas stimulation with db-cAMP produced an increase that was most pronounced when low concentrations of hydroxyzine had been used. It is suggested that H1-receptor antagonists do not inhibit stimulation of acid production in the secretory canaliculi. They may, however, interfere with a mechanism preventing acid from leaving the parietal cell. Such a mechanism may contribute to the delay in appearance of acid in the gastric lumen after stimulation of gastric acid production.

Aminopyrine↗
PubMed1987

The aminopyrine breath test, an inadequate early indicator of methotrexate-induced liver disease in patients with psoriasis.

The aminopyrine breath test has been shown to be a sensitive noninvasive indicator of liver cell dysfunction. In a search for a noninvasive method of monitoring the effects of methotrexate therapy, we have investigated the use of the aminopyrine breath test in patients receiving methotrexate for the treatment of severe psoriasis. The [14C]-aminopyrine breath test was performed in 20 normal control subjects, 32 patients with psoriasis receiving methotrexate therapy, and 8 patients with histologically confirmed cirrhosis of differing etiology. Eighteen patients on methotrexate had liver biopsies classified as grade I changes, 6 patients as grade II, and 8 patients as grade III. The normal value for the breath test was 11.0 +/- 1.6% (mean +/- 1 SD). The mean [14C]-CO2 excretion (8.3 +/- 4.4%) of the 8 patients with grade III liver disease was significantly different from the control subjects (p less than 0.02), and those with grade I liver changes (p less than 0.04). The aminopyrine breath test was only able to detect the later severe stages of methotrexate hepatotoxicity, grade III, when fibrosis occurs, before established cirrhosis was present. Our data suggests that the aminopyrine breath test is not a sensitive indicator for the detection of early methotrexate-induced hepatotoxicity, (stages I and II), but will detect the precirrhotic stage III change. Consequently, we recommend that a liver biopsy should be performed annually in all psoriatic patients receiving methotrexate, to detect histological damage, especially when the aminopyrine breath test score falls below the 95% confidence limits of normal.

Aminopyrine↗
PubMed1987

Strain differences in susceptibility to the embryotoxic effects of aminopyrine in mice.

Embryotoxic effects induced by aminopyrine were studied in two inbred strains of mice, C57BL/6N and DBA/2N. Aminopyrine was given by subcutaneous injection at a dose of 200 mg/kg on day 7, 8 and 9 of gestation. In both strains, aminopyrine-induced malformations such as omphalocele, club foot and kinky tail were observed, but the incidence of malformations was significantly higher in C57BL/6N than in DBA/2N. Maternal plasma levels of aminopyrine and its metabolites were significantly higher in C57BL/6N, compared to DBA/2N. Further, reciprocal crosses between these two strains were used to clarify whether the maternal or fetal genotype is more important in aminopyrine-induced embryotoxicity. F1 hybrid embryos developing in C57BL/6N or DBA/2N mothers were as resistant as inbred DBA/2N. These results suggest that strain differences in susceptibility to aminopyrine may depend on fetal genotype rather than maternal factors.

Aminopyrine↗
PubMed1976

Aminopyrine demethylation measured by breath analysis in cirrhosis.

The method of measuring the rate of aminopyrine demethylation by breath analysis was assessed in 23 normal subjects and 20 patients with cirrhosis. Carbon 14 aminopyrine specifically labeled at the two N-methyl groups was administered by mouth in a dose of 9 mg/kg, including a total radioactivity of 2 muCi. The decay of the specific activity of 14CO2 in breath (kb) was found to correlate (r = 0.91) with the disappearance of aminopyrine from plasma (KP). In normal volunteers, kb was 22.4%/hr; in patients with alcoholic and nonalcoholic cirrhosis it was depressed to 8.4%/hr (p less than 0.001). The degree of functional impairment found with the breath test was similar to the sulfobromophthalein (BSP) disappearance curve and the galactose elimination capacity. Although many questions relating to the aminopyrine breath test remain open, our data confirm and extend previous studies of 14CO2 breath analysis after 14C-aminopyrine administration. It is concluded that it represents a simple and noninvasive procedure which quantitatively reflects the microsomal function of the cirrhotic liver.

Adult↗
PubMed1999

Contribution of human hepatic cytochrome P450s and steroidogenic CYP17 to the N-demethylation of aminopyrine.

1. Aminopyrine N-demethylase activity was determined for 11 forms of human hepatic cytochrome P450s (P450s) expressed in yeast Saccharomyces cerevisiae and for human steroidogenic CYP17 expressed in Escherichia coli. 2. Among the hepatic P450s, the N-demethylation of aminopyrine was catalysed most efficiently by CYP2C19, followed by CYP2C8, 2D6, 2C18 and 1A2, whereas the activity with CYP2E1 was negligible. The kinetics of the N-demethylation process by CYP1A2, 2C8, 2C19 and 2D6 were studied by fitting to Michaelis-Menten kinetics by Lineweaver-Burk plots. CYP2C19 exhibited the highest affinity and a high capacity for the aminopyrine N-demethylation. CYP2C8 showed the highest Vmax, followed by CYP2C19, 2D6 and 1A2, whereas the Km for CYP2C8, 2D6 and 1A2 were 10-17 times higher than that for CYP2C19. Accordingly, the Vmax/Km for CYP2C19 was more than nine times higher than that of other P450s. 3. Human steroidogenic CYP17 also catalysed aminopyrine N-demethylation and the activity was comparable with that for CYP3A4 which is a dominant P450 in human liver. The activity was increased 1.5-fold by the addition of cytochrome b5, whereas the activity was not affected by the addition of Mg2+. 4. These results suggest that several human hepatic P450s, especially CYP2C19, and steroidogenic CYP17 exhibit aminopyrine N-demethylase activity.

Aminopyrine↗
PubMed1976

Aminopyrine disposition: studies on breath, saliva, and urine of normal subjects and patients with liver disease.

To investigate aminopyrine disposition, breath, saliva, and urine were collected from 25 control patients, 15 patients with hepatocellular disease, and 26 patients with hepatic neoplasm after oral administration of 2 muCi [14C]aminopyrine. The percentage 14C excreted in breath 14CO2 in 2 hr (aminopyrine breath test, ABT) correlated with the breath 14CO2 elimination rate (r = 0.92, p less than 0.01), with the aminopyrine metabolic clearance rate (MCR) (r = 0.85, p less than 0.01), and with the plasma half-life of 4-aminoantipyrine (r = -0.54, p less than 0.05). The ABT permits study of aminopyrine disposition with simplicity, accuracy, and safety.

Adult↗
PubMedDate not supplied

Recovery of liver function in partially hepatectomized rats evaluated by aminopyrine demethylation capacity.

Aminopyrine demethylation was investigated in rats after a 70% hepatectomy to assess possible parallelism between the recovery of mass and function. Tests were performed by analyzing 14CO2 exhalation from 0.1 microCi per 100 gm of body weight of [dimethylamine-14C]aminopyrine given intraperitoneally with incremental doses of unlabeled drug. Early after 70% hepatectomy, Vmax was reduced by 52%. This discordance between mass and function was not due to extrahepatic aminopyrine demethylation, since liver exclusion reduced demethylation of aminopyrine to nearly nil. Whether it results from increased liver blood flow in the remnant liver is less clear: portacaval anastomosis provoked an identical fall in Vmax and liver blood flow, but aortal-portal fistula which increased liver blood flow by 70% did not modify Vmax. The early increase in Vmax could be related to a "hepatotrophic" factor of splanchnic origin which increased after partial hepatectomy and decreased after portacaval shunt. After the early period, Vmax, expressed per gram of actual liver weight, returned to control range. Throughout regeneration (4 to 144 hr), no modification was observed in Km nor in cytochrome P-450 concentration. Enzymatic induction with phenobarbital increased the demethylation capacity more than liver weight in intact and regenerating liver. Except for the first hours after partial hepatectomy or after enzymatic induction, the aminopyrine demethylation capacity directly correlated with liver mass and may be useful in evaluating liver regeneration in vivo.

Aminopyrine↗