A substantial number of the world's population continues to smoke tobacco, even in the setting of a cancer diagnosis. Studies have shown that cancer patients with a history of smoking have a worse prognosis. Modulation of several physiologic processes involved in drug disposition has been associated with chronic exposure to tobacco smoke. The most common of these can be categorized into effects on cytochrome P450 mediated metabolism, glucuronidation, and protein binding. Perturbation in the pharmacokinetics of anticancer drugs could result in clinically significant consequences, given they are amongst the most toxic, but potentially beneficial, pharmaceuticals prescribed. Unfortunately, the effect of tobacco smoking on drug disposition has only been explored for a few marketed anticancer drugs, thus very little prescribing information is available to guide clinicians on the vast majority of compounds. The carcinogenic properties of multiple compounds found in tobacco smoke have been well studied, however relatively little attention has been given to the effects of nicotine itself on cancer growth. Emerging data are available which identify nicotine's effects on cancer cell apoptosis, tumor angiogenesis, invasion, and metastasis. The implications of such are unclear, but may lead to important questions to be addressed regarding approaches to smoking cessation in cancer patients.

Elimination of hydrogen sulfide from glutathione (GSH) converts a well-known cellular nucleophile to an electrophilic species, γ-glutamyldehydroalanylglycine (EdAG). We have found that a sulfonium metabolite formed from GSH and busulfan undergoes a facile β-elimination reaction to give EdAG, which is an αβ-unsaturated dehydroalanyl analog of GSH. EdAG was identified as a metabolite of busulfan in a human liver cytosol fraction. EdAG condenses with GSH in a Michael addition reaction to produce a lanthionine thioether (GSG), which is a non-reducible analog of glutathione disulfide (GSSG). EdAG was less cytotoxic than busulfan to C6 rat glioma cells. GSH and EdAG were equally effective in displacing a glutathione S-transferase isozyme (human GSTA1-1) from a GSH-Agarose column. The finding of an electrophilic metabolite of GSH suggests that alteration of cellular GSH concentrations, irreversible non-reducible glutathionylation of proteins, and interference with GST function may contribute to the toxicity of busulfan.

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While the liver is the primary site of metabolism and biliary excretion for many medications, data are limited on the liver’s pharmacokinetic abilities in cirrhosis. Cirrhosis develops through collagen deposition eventually culminating in end-stage liver disease that compromises hepatic drug metabolism. Consequently, the United States Food and Drug Administration (US FDA) recommends evaluating the pharmacokinetics of medications in subjects with hepatic impairment if hepatic metabolism constitutes more than 20% of their elimination or if they have a narrow therapeutic range. A variety of noninvasive indices and radiologic procedures can be employed to assess hepatic drug metabolism and excretion. The Child-Pugh score is the most commonly used scale for assessing hepatic impairment among drugs submitted for US FDA approval. The score, originally developed to guide operative mortality in patients undergoing hepatic resection, has not been modified since its inception five decades ago. Furthermore, the score was not originally intended to be a guide for potential dose modification in patients with hepatic impairment. These reasons, in combination with the availability of a variety of new imaging modalities and an enhanced understanding of hepatic biology, should foster the development of novel methods to assess the effect of hepatic impairment on liver drug metabolism.

A recirculation chain incorporated in a multi-compartment pharmacokinetic model of irinotecan and its metabolites appears to improve characterization of this drug's disposition in patients with glioma.