Relationship between the metabolism of antipyrine, hexobarbitone and theophylline in man as assessed by a ‘cocktail’ approach.

Schellens, J.H.M.; Wart, JH van der; Danhof, Meindert; Velde, EA van der; Breimer, D.D.

doi:10.1111/j.1365-2125.1988.tb03394.x

Cited by 53 publications

(41 citation statements)

References 27 publications

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“…Half the subjects received LPS in the initial clearance study followed by the saline control study at least 2 wk later. For each clearance study, AP (250 mg), HB (500 mg), and TH (150 mg) were given as a "cocktail" (23,24) after an overnight fast. For the LPS drug clearance study, each subject received two i.v.…”

Section: Methodsmentioning

confidence: 99%

“…LPS administration to volunteers has been performed in a number of recent studies describing the physiologic responses of sepsis (18)(19)(20)(21)(22)). In the current study, male volunteers ingested a "cocktail" of three probe drugs including antipyrine (AP),' hexobarbital (HB), and theophylline (TH) (23,24) whose clearances were measured on one occasion after saline injections and on another occasion after two LPS injections. This study demonstrates that even the relatively minor inflammatory response that occurred after this small dose of LPS was enough to decrease clearances of the probe drugs by 22-35%.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Endotoxin administration to humans inhibits hepatic cytochrome P450-mediated drug metabolism.

Shedlofsky¹,

Israel²,

McClain³

et al. 1994

J. Clin. Invest.

198

114

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In experimental animals, injection of gram-negative endotoxin (LPS) decreases hepatic cytochrome P450-mediated drug metabolism. To evaluate this phenomenon in a human model of gram-negative sepsis, LPS was administered on two consecutive days to healthy male volunteers during which time a cocktail of antipyrine (AP-250 mg), hexobarbital (HB-500 mg), and theophylline (TH-150 mg) was ingested and the apparent oral clearance of each drug determined. Each subject had a control drug clearance study with saline injections. In the first experiment, six subjects received the drug cocktail 0.5 h after the first dose of LPS. In the second experiment, another six subjects received the drug cocktail 0.5 h after the second dose of LPS. In both experiments, LPS caused the expected physiologic responses of inflammation including fever with increases in serum concentrations of TNFa, IL-113, IL-6, and acute phase reactants. In the first experiment, only minor decreases in clearances of the probe drugs were observed (7-12%). However in the second experiment, marked decreases in the clearances of AP (35, 95% CI 18-48%), HB (27, 95% CI 14-34%), and TH (22, 95% CI 12-32%) were seen. The decreases in AP clearance correlated with initial peak values of TNFat (r = 0.82) and IL-6 (r = 0.86). These data show that in humans the inflammatory response to even a very low dose of LPS significantly decreases hepatic cytochrome P450-mediated drug metabolism and this effect evolves over a 24-h period. It is likely that septic patients with much higher exposures to LPS have more profound inhibition of drug metabolism. (J.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Endotoxin administration to humans inhibits hepatic cytochrome P450-mediated drug metabolism.

Shedlofsky¹,

Israel²,

McClain³

et al. 1994

J. Clin. Invest.

198

114

View full text Add to dashboard Cite

show abstract

“…Considering that total clearance or clearance for production of metabolites reflects the activity of the enzyme, correlation and orthogonal regression analyses may indicate that the substrates or metabolites studied are oxidized and respectively formed by the same or similar CYP isoforms (20).…”

Section: Resultsmentioning

confidence: 99%

“…The plasma concentration (+)-ASOX/(-)-ASOX ratios were analyzed using the paired t-test, with the level of significance set at P≤0.05. Correlation and orthogonal regression analyses were performed according to the equations described by Schellens et al (20).…”

Section: Discussionmentioning

confidence: 99%

Albendazole metabolism in patients with neurocysticercosis: antipyrine as a multifunctional marker drug of cytochrome P450

Marques

Takayanagui

Lanchote

2002

Braz J Med Biol Res

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The present study investigates the isoform(s) of cytochrome P450 (CYP) involved in the metabolism of albendazole sulfoxide (ASOX) to albendazole sulfone (ASON) in patients with neurocysticercosis using antipyrine as a multifunctional marker drug. The study was conducted on 11 patients with neurocysticercosis treated with a multiple dose regimen of albendazole for 8 days (5 mg/kg every 8 h). On the 5th day of albendazole treatment, 500 mg antipyrine was administered po. Blood and urine samples were collected up to 72 h after antipyrine administration. Plasma concentrations of (+)-ASOX, (-)-ASOX and ASON were determined by HPLC using a chiral phase column and detection by fluorescence. The apparent clearance (CL/f) of ASON and of the (+) and (-)-ASOX enantiomers were calculated and compared to total antipyrine clearance (CL T ) and the clearance for the production of the three major antipyrine metabolites (CL m ). A correlation (P≤0.05) was obtained only between the CL T of antipyrine and the CL/f of ASON (r = 0.67). The existence of a correlation suggests the involvement of CYP isoforms common to the metabolism of antipyrine and of ASOX to ASON. Since the CL T of antipyrine is a general measure of CYP enzymes but with a slight to moderate weight toward CYP1A2, we suggest the involvement of this enzyme in ASOX to ASON metabolism in man. The study supports the establishment of a specific marker drug of CYP1A2 in the study of the in vivo metabolism of ASOX to ASON.

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“…Indocyanine green (ICG) and bromsulphthalein (BSP) both have high hepatic extraction ratios in subjects with normal liver function, and their clearance rates have been used as surrogate measures of liver blood flow [1][2][3][4]. Intrinsic clearance associated with the activity of the cytochrome P-450 enzyme system has been assessed from antipyrine clearance [22][23][24] and, more recently, from the formation clearances to antipyrine metabolites [9][10][11][12].…”

Section: Discussionmentioning

confidence: 99%

Liver blood flow, antipyrine clearance, and antipyrine metabolite formation clearance in patients with chronic active hepatitis and alcoholic cirrhosis.

Bauer

O’Sullivan

Reiss

et al. 1994

Brit J Clinical Pharma

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1 Duplex scanning was used to measure liver blood flow (hepatic artery and main branches of the portal and hepatic veins) in six healthy subjects, five cirrhotic patients, and six hepatitis patients. Antipyrine clearance and formation clearances to its metabolites were also measured. 2 Compared with healthy control subjects, cirrhotic patients had a lower hepatic vein blood flow (-76%, P < 0.05). This was due primarily to a lower portal vein blood flow (-36%, NS). A statistically significant difference in liver blood flow between patients with hepatitis and normal subjects was not detected. 3 Antipyrine half-life, clearance, and the area under the serum drug concentration vs time curve were significantly different in cirrhotic patients compared with the healthy subjects (mean ± s.d.-healthy controls: t, 2 = 13.7 ± 3.0 h, CL = 30.0 ± 8.6ml h-' kg-', AUC = 549 ± 139 mg 1-1 h; cirrhotic patients: ti,2 = 32.4 ± 1.7 h, CL = 12.3 ± 2.1 ml h-1 kg-', AUC = 1061 ± 218 mg 1-1 h; P < 0.008). Antipyrine halflife, clearance, and the area under the serum drug concentration vs time curve were not significantly different in hepatitis patients compared with the healthy subjects (hepatitis patients: tb = 14.3 ± 3.7 h, CL = 29.3 ± 8.5 ml h-1 kg-I, AUC = 498 ± 142 mg I1-h). The volume of distribution of antipyrine was similar in all three groups of subjects. 4 Formation clearances to 3-OH-methylantipyrine, 4-OH-antipyrine, and norantipyrine were all lower (P < 0.009) in cirrhotic patients compared with normal subjects and hepatitis patients. However, only the formation clearance to norantipyrine was lower (P < 0.002) in hepatitis patients when compared with normals. 5 There were strong correlations between the logarithmic transformations of the formation clearances for all antipyrine metabolites (r = 0.88-0.93, P < 0.0001). However, the only orthogonal regression line with a slope not significantly different from one was that for norantipyrine and 3-OH-methylantipyrine indicating that these two metabolites may be metabolized by a common enzyme(s). 6 Weak correlations were found between the logarithmic transformations of hepatic vein blood flow and antipyrine clearance and the logarithmic transformations of hepatic vein blood flow and formation clearances to antipyrine metabolites (r= 0.54-0.62, P < 0.05). 7 Cirrhotic patients may have difficulty metabolizing drugs with high hepatic extraction ratios or drugs that are eliminated by the same liver enzyme systems which produce the three major metabolites of antipyrine. Hepatitis patients may have difficulty metabolizing drugs that share the same hepatic enzyme system responsible for the formation of norantipyine from antipyrine.

show abstract

Relationship between the metabolism of antipyrine, hexobarbitone and theophylline in man as assessed by a ‘cocktail’ approach.

Cited by 53 publications

References 27 publications

Endotoxin administration to humans inhibits hepatic cytochrome P450-mediated drug metabolism.

Endotoxin administration to humans inhibits hepatic cytochrome P450-mediated drug metabolism.

Albendazole metabolism in patients with neurocysticercosis: antipyrine as a multifunctional marker drug of cytochrome P450

Liver blood flow, antipyrine clearance, and antipyrine metabolite formation clearance in patients with chronic active hepatitis and alcoholic cirrhosis.

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