PubMed · 976091
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1976-06-18. Para-seltzer.. https://pubmed.ncbi.nlm.nih.gov/976091/
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The pharmacokinetics of acetaminophen have been well studied in different populations, especially in Caucasians. However, limited studies on acetaminophen pharmacokinetics have been conducted in the native Chinese and few such data have been reported in the English language literature. Previous published studies suggested that environmental and genetic factors may cause inter-individual difference in acetaminophen disposition, thus we investigated the pharmacokinetics of acetaminophen in Hong Kong Chinese subjects. A single 500 mg oral dose of acetaminophen was administered to 12 healthy male Chinese subjects under fasting conditions. Multiple blood samples were obtained after drug administration. Plasma acetaminophen concentrations were determined using HPLC, and its main pharmacokinetic parameters were generated. In comparison to other published data, acetaminophen half-life was considerably longer (15-62%), and oral clearance was lower (16-56%) in Hong Kong Chinese as compared to Australian Chinese, Caucasians (USA, UK, Australia), and subjects from Pakistan, Denmark, Spain and South Africa. Similarities however were found in the pharmacokinetic parameters between Hong Kong Chinese and Mainland Chinese subjects. The observed pharmacokinetic parameters of acetaminophen in Hong Kong Chinese subjects may be different from other ethnic populations. Further studies are needed to verify this hypothesis.
In patients suspected of having drug-induced immune thrombocytopenia, antibodies reactive with normal platelets in the presence of the suspect drug can sometimes be identified, but negative results are often obtained. One reason for this is that drug metabolites, formed in vivo, can be the sensitizing agents, but very little is known about the specific metabolites that can cause this complication. Five patients were studied who developed thrombocytopenia after taking the nonsteroidal anti-inflammatory drug naproxen (3 cases) or acetaminophen (2 cases) but in whom drug-dependent antibodies could not be detected by means of the unmodified drugs. In each case, antibodies that reacted with normal target platelets in the presence of a known drug metabolite (naproxen glucuronide or acetaminophen sulfate) were identified. Four of the antibodies were specific for the glycoprotein (GP) IIb/IIIa complex, but one acetaminophen sulfate-dependent antibody reacted preferentially with GPIb/IX/V. In patients with a clinical picture suggestive of drug-induced immune thrombocytopenia, tests for metabolite-dependent antibodies can be helpful in identifying the responsible agent. (Blood. 2001;97:3846-3850)
Most chemical carcinogens require metabolic activation to electrophilic metabolites that are capable of binding to DNA and causing gene mutations. Carcinogen metabolism is carried out by large groups of xenobiotic-metabolizing enzymes that include the phase I cytochromes P450 (P450) and microsomal epoxide hydrolase, and various phase II transferase enzymes. It is extremely important to determine the role P450s play in the carcinogenesis and to establish if they are the rate limiting and critical interface between the chemical and its biological activities. The latter is essential in order to validate the use of rodent models to test safety of chemicals in humans. Since there are marked species differences in expressions and catalytic activities of the multiple P450 forms that activate carcinogens, this validation process becomes especially difficult. To address the role of P450s in whole animal carcinogenesis, mice were produced that lack the P450s known to catalyze carcinogen activation. Mouse lines having disrupted genes encoding the P450s CYP1A2, CYP2E1, and CYP1B1 were developed. Mice lacking expression of microsomal epoxide hydrolase (mEH) and NADPH-quinone oxidoreductase (NQO1) were also made. All of these mice exhibit no gross abnormal phenotypes, suggesting that the xenobiotic-metabolizing enzymes have no critical roles in mammalian development and physiological homeostasis. This explains the occurrence of polymorphisms in xenobiotic-metabolizing enzymes among humans and other mammalian species. However, these null mice do show differences in sensitivities to acute chemical toxicities, thus establishing the importance of xenobiotic metabolism in activation pathways that lead to cell death. Rodent bioassays using null mice and known genotoxic carcinogens should establish whether these enzymes are required for carcinogenesis in an intact animal model. These studies will also provide a framework for the production of transgenic mice and carcinogen bioassay protocols that may be more predictive for identifying the human carcinogens and validate the molecular epidemiological studies ongoing in humans that seek to establish a role for polymorphisms in cancer risk.