Current Drug Metabolism - Volume 11, Issue 6, 2010

Positron emission tomography (PET) is a very sensitive molecular imaging technique that when employed with an appropriate radioligand has the ability to quantititate physiological processes in a non-invasive manner. Since the imaging technique detects all radioactive emissions in the field of view, the presence and biological activity of radiolabeled metabolites must be determined for each radioligand in order to validate the utility of the radiotracer for measuring the desired physiological process. Thus, the identification of metabolic profiles of radiolabeled compounds is an important aspect of design, development, and validation of new radiopharmaceuticals and their applications in drug development and molecular imaging. Metabolite identification for different chemical classes of radiopharmaceuticals allows rational design to minimize the formation and accumulation of metabolites in the target tissue, either through enhanced excretion or minimized metabolism. This review will discuss methods for identifying and quantitating metabolites during the pre-clinical development of radiopharmaceuticals with special emphasis on the application of LC/MS.

Dihydrocodeine (DHC) is a semi-synthetic analogue of codeine which was formed by the hydrogenation of the double tie in the main chain of the codeine molecule. DHC is used as an analgesic, antitussive and antidiarrhoeal agent; it is also used for the treatment of opioid addiction. Limited data is available on the relative potency of DHC to other opioids. The analgesic effect of DHC is probably twice as potent as codeine for the parenteral and slightly stronger for an oral route. DHC possesses approximately 1/6th of the morphine analgesic effect when drugs are administered orally. In this article pharmacokinetics, pharmacodynamics, dosing guidelines, adverse effects and clinical studies of DHC in pain management are shown with focus on cancer pain. The impact of CYP2D6 activity on DHC analgesia was discussed and a proposal of calculation equianalgesic doses of DHC to other opioids was put forward.

Cisplatin is one of the commonly-used chemotherapeutic drugs to efficiently treat malignant tumors in clinic, however, the adverse effects of cisplatin such as nephrotoxicity, neurotoxcity, and hemolytic uremic syndrome are often observed at its clinical doses (~60 mg/m2), which limit its broader application. In earlier studies, little attention was paid to the subtle changes in the architecture of lymphatic organs after low doses of cisplatin treatment. This paper reviews current understanding of cisplatin-induced erythrocyte injury, and presents our latest finding that a low dose of cisplatin (3.6 mg/m2/day, 14 days) could induce specific hemosiderin deposition in spleen of both normal and hepatoma-22 (H22) inoculated Balb/C mice. This dose of cisplatin significantly inhibited H22-induced acute ascites development. No significant toxicity was induced by this dose of cisplatin to tissues except for hemosiderin accumulation in the spleen of both normal and H22 tumor-bearing mice. Increased splenic iron content and erythrocyte injury were observed after treatment with the low dose of cisplatin. The mRNA levels of ferroportin (FPN1) and ferritin were upregulated by 25 and 5-fold in spleen, respectively. Overexpression of FPN1 and ferritin protein were also been observed at protein levels by Western blotting analysis. In addition, the mRNA expression of hepcidin was also increased, suggesting blockage of iron recycling through FPN1 in spleen with cisplatin treatment. In conclusion, cisplatin treatment damages the erythrocytes which accumulate in the red pulp of spleen with defective recycling of FPN1 and ferritin protein. Hepcidin inhibits the function of FPN1 as iron-exporter leading to iron overloaded inside ferritins of splenic cells, which are stained with abnormal hemosiderin accumulation. These results demonstrate that cisplatin-caused hemosiderin deposition in spleen provides a valuable clue for understanding the molecular basis of toxicity of cisplatin and hemosiderin accumulation and iron metabolism in vivo.

Background: The metabolic/biotransformation pathways of atypical antipsychotics (aripiprazole, clozapine, iloperidone, olanzapine, paliperidone, quetiapine, risperidone, and ziprasidone) have been characterized and reviewed. However, comparisons of excretory pathways remain unexplored. Objective: To analyze the excretion profile of atypical antipsychotic agents and compare the overall magnitude of metabolism (changed vs. unchanged drug) and route of excretion (feces vs. urine). Secondary objectives include providing: 1) dosing information in hepatic and renal impairment, and 2) context of the specific enzymes and pathways involved in each agent's biotransformation. Methods: Published literature and each manufacturer's radiolabeled drug absorption, distribution, metabolism and excretion data and U.S. prescribing information were reviewed. Results: With the exception of paliperidone, atypical antipsychotics undergo extensive metabolism (i.e.,≤50% of dose recovered unchanged). Quetiapine undergoes the greatest overall metabolism (<1% of the dose recovered unchanged) and paliperidone the least (59% recovered unchanged in the urine). Between-agent differences exist in the extent of cytochrome P450 (CYP450) metabolism and the specific isozymes involved. After administration of a radioactive dose, fecal elimination of unchanged drug plus metabolites ranged from 11% (paliperidone) to 71% (ziprasidone) and renal elimination ranged from 21% (ziprasidone) to 80% (paliperidone). Conclusions: Understanding the differences in the elimination profiles of atypical antipsychotics agents may permit better-informed drug and dose selection in special populations such as those with comorbid conditions (e.g. hepatitis, diabetes, end-stage renal disease) or pharmacogenetic variability; or at risk for drug-drug interactions. The use of patient tailored drug and dose-selection may result in greater treatment efficacy and a reduction in adverse events.

An understanding of dose proportionality is essential in drug development, and the results are of great clinical importance for predicting the effects of dose adjustments. However, little consensus exists with regard to study design and analysis. The aim of this paper was to produce a detailed profile of the information on dose proportionality studies in the last 10 years and to provide a foundation for reflection and debate on future priorities. A total of 147 publications comprising 156 studies were analyzed. The typical dose proportionality study enrolled 20 to 30 subjects and randomly allocated them into 3 to 4 dose levels to investigate pharmacokinetic behaviors within a dose ratio range of 2-6. The most common design was the crossover experiment (52.6%), and evaluating dose-adjusted pharmacokinetic parameters followed by hypothesis testing (43%) was the most frequent statistical approach. However, the alternative crossover design and equivalence criterion based on the power model represented only 4% and 8% of studies, respectively. The power model as a recommendable empirical relationship to assess dose proportionality was applied in 25 (16%) studies. This research suggests that the alternative crossover design and power model statistical method should be attracting more attention in order to obtain more information in studies with limited subjects.

Cytosolic sulfotransferases (SULTs) are traditionally known as the Phase II drug-metabolizing or detoxifying enzymes that serve for the detoxification of drugs and other xenobiotics. These enzymes in general catalyze the transfer of a sulfonate group from the active sulfate, 3'-phophoadenosine 5'-phosphosulfate (PAPS), to low-molecular weight substrate compounds containing hydroxyl or amino group(s). Despite considerable efforts made in recent years, some fundamental aspects of the SULTs, particularly their ontogeny, cell type/tissue/organ-specific distribution, and physiological relevance, particularly their involvement in drug metabolism and detoxification, still remain poorly understood. To better understand these fundamental issues, we have embarked on developing the zebrafish as a model for studies concerning the SULTs. To date, fifteen zebrafish SULTs have been cloned, expressed, purified, and characterized. These zebrafish SULTs, which fall into four major SULT gene families, exhibited differential substrate specificities and distinct patterns of expression at different stages during embryogenesis, through larval development, and on to maturity. The information obtained, as summarized in this review, provides a foundation for further investigation into the physiological and pharmacological involvement of the SULTs using the zebrafish as a model.

Chirality is a ubiquitous feature present in all biological systems that plays a very important role in many processes. Drug metabolism is one of these and is the subject of this review. Chiral drugs can be metabolized without changes in their chiral characteristics, but also their biotransformation may give rise to a new chiral center. On the other hand, prochiral drugs are always metabolized to chiral metabolites. The ratio of formed enantiomers/diastereoisomers is the constant known as enzyme stereospecificity, and this is as important a characteristic for each enzyme-substrate pair as is the Michaelis constant. Drugs are often substrates for multiple biotransformation enzymes, and all enzymes involved may metabolize a chiral or prochiral drug with different stereospecificity so that variant enantiomer ratios are achieved. Enzyme stereospecificity of whole cell fraction is the sum of the stereospecificities of all enzymes participating in metabolism of a substrate. Differing stereospecificities in the metabolism of a drug between whole cell fraction and enzymes point to the contribution of other enzymes. Using several drugs as examples, this review shows that enzyme stereospecificity can serve as a powerful tool in searching for new biotransformation enzymes. Although it is not often used in this way, it is clear that this is possible. There are today drugs with well-known chiral metabolism, but, inasmuch as many xenobiotics are poorly characterized in terms of chiral metabolism, enzyme stereospecificity could be widely utilized in researching such substances.

This addendum was compiled by the authors to clarify some points presented in the review article titled “Expression, Function and Regulation of Mouse Cytochrome P450 Enzymes: Comparison With Human Cytochrome P450 Enzymes”, which appeared in Current Drug Metabolism (2009) 10 (10), 1151-1183. Table 1 lists Cyp2c22, Cyp2c23, Cyp2c51 and Cyp2b20 as mouse P450 genes. Mouse Cyp2c22 and Cyp2c23 genes (ref. 440) should not be included in Table 1 because they are believed to be the same as Cyp2c70 and Cyp2c44, respectively (see mouse Master Table in Dr. Nelson's P450 homepage, http://drnelson.uthsc.edu/mouse.table.html). The mouse Cyp2c51 gene (ref. 119) is probably a combination of mouse Cyp2c52-ps and Cyp2c69 genes and may not be a separate gene (see Dr. Nelson's P450 homepage). The mouse Cyp2b20 gene (Swiss-Prot accession number Q62397) may be identical with Cyp2b10, although recent studies (refs. 9, 60 and 180) have suggested that Cyp2b20 and Cyp2b10 may be different genes. This matter remains to be resolved. If the following mouse P450 genes, Cyp2c22, Cyp2c23, Cyp2c51 and Cyp2b20, are removed from Table 1 and the Cyp2ab1 gene (which is not a pseudogene, ref. 8) is added, then the total mouse P450 gene count would be 102 genes, as originally reported in ref. 8, and not 105 genes as stated on page 1151. With regard to the human cytochrome P450 data presented in Table 2, CYP4F3A and CYP4F3B enzymes were generated by alternative splicing of the CYP4F3 gene that encodes the CYP4F3 enzyme (ref. 174). Thus, CYP4F3A and CYP4F3B enzymes are not encoded by separate cytochrome P450 genes. It thus appears that there are 57 human P450 genes, as originally reported in ref. 8, and not 58 genes as stated on page 1151. In addition to the human P450 enzymes listed in Table 2, additional human P450 enzymes have been discovered as a result of gene splicing. The authors are indebted to Drs. Daniel Nebert and David Nelson for their expert advice on the subject matter presented in this addendum.