Benzo(a)pyrene Metabolism and Plasma Elimination Rates of Phenacetin, Acetanilide and Theophylline in Man

Abstract

The plasma elimination rates of phenacetin, acetanilide and theophylline have been determined in 32 healthy subjects in an effort to find drugs resembling in their metabolism the carcinogen benzo(a)pyrene. The plasma half-lives and metabolic clearance rates of the three drugs were correlated with the inducibilities of aryl hydrocarbon hydroxylase (AHH) in mitogen-stimulated lymphocytes and the plasma half-lives and metabolic clearance rates of antipyrine determined in previous studies. Statistically significant correlations were found between the half-lives and metabolic clearance rates of phenacetin, acetanilide and theophylline and the AHH ratios except for the metabolic clearance rates of phenacetin which did not correlate. The correlations of the three drugs with the half-lives and metabolic clearance rates of antipyrine were equally good. Of all the drugs tested thus far for similarity in metabolism to benzo(a)pyrene, antipyrine showed the best association followed closely by theophylline.

Unravelling the pharmacokinetics of aflatoxin B1: In vitro determination of Michaelis–Menten constants, intrinsic clearance and the metabolic contribution of CYP1A2 and CYP3A4 in pooled human liver microsomes

“…When using the AAF for CYP1A2 to the obtained values of AFB1 in HLM and in rhCYPs, hepatic blood clearances of 38.5 L/h and 56.1 L/h were obtained, respectively ( Table 3 ). Applying the CYP1A2 AAF to the experimentally determined CL H,int,u , a CL H,B for PH of 21.7 L/h was achieved which is close to the in vivo human hepatic blood clearance of 20.8 L/h reported by Shibata et al (2002) and lies within the range reported by Kellermann and Luyten-Kellermann (1978; Table 5) .…”

“… e Shibata et al (2002) . f Kellermann and Luyten-Kellermann (1978) . AFB1, aflatoxin B1; B:P, blood to plasma ratio; CL H,B , hepatic blood clearance; CL H , p , hepatic plasma clearance; CYP, cytochrome P; f u,B , free fraction in blood; f u,mic , free microsomal fraction; HLM, human liver microsomes; MDZ, midazolam; PH, phenacetin; rhCYP, recombinant enzyme system.…”

Large Theophylline Requirements due to High Theophylline Clearance: Verification by the Antipyrine Test

“…Evalua- tion o f the pattern o f antipyrine metabolite formation suggested induced formation o f all three antipyrine metabolites, but dispropor tionate induction o f hydroxylated metabo lites (4-hydroxy and 3-hydroxymethyl deriv atives) as opposed to the demethylated deriv ative. It is noteworthy that cigarette smoking reportedly increases clearance o f these me tabolites to a greater extent than the norantipyrine metabolite [17], The microsomal en zymes responsible for the formation o f these metabolites may be similar to those responsi ble for the metabolism o f benz[a]pyrene as well as theophylline [3]. Phénobarbital, how ever, also induces the metabolism o f antipy rine, but does so via induction o f the noran- tipyrine and 4-hydroxyantipyrine pathways to a greater extent than that o f the 3-hydroxymethyl pathway [18].…”

“…The principal metabolites formed are 3-methyl xanthine, 1-methyluric acid and 1,3-dimethyluric acid, respectively [9], The ophylline clearance can be induced by a vari ety o f agents including rifampicin, cigarette smoke, benz[a]pyrene, charcoal, alcohol, phenytoin and sulfinpyrazone [1][2][3][10][11][12][13][14], Phénobarbital, however, has a relatively small influence on the clearance o f theophyl line [2].…”

“…Theophylline is a commonly used bronchodilator whose clearance is affected by many factors including coadministration of other drugs [1][2][3], We report a case o f an asthmatic man whose large theophylline re quirements were related to induction o f his hepatic monooxygenase drug metabolizing enzyme system as verified by the antipyrine test [4,5],…”