Genotoxicity and carcinogenicity studies of analgesics, anti-inflammatory drugs and antipyretics

Abstract

This survey is a compendium of genotoxicity and carcinogenicity information of analgesics, anti-inflammatory drugs and antipyretics. Data from 120 drugs were collected; 109 of them are still in the market. Of these 120 drugs, 58 (48.3%) do not have retrievable genotoxicity or carcinogenicity data. The remaining 62 (51.7%) have at least one genotoxicity or carcinogenicity test result. Of these 62 drugs, 31 have at least one positive finding: 26 tested positive in at least one genotoxicity assay, 13 in at least one carcinogenicity assay, and 8 gave a positive result in both at least one genotoxicity assay and at least one carcinogenicity assay. In terms of correlation between results of the various genotoxicity assays and absence of carcinogenic activity in mice and/or rats or in other species, 12 of 23 non–carcinogenic drugs tested positive in at least one of the various genotoxicity assay systems. Concerning the predictivity of genetic toxicology findings for the result(s) of long-term carcinogenesis assays, 35 drugs have both genotoxicity and carcinogenicity data: 11 of them (31.4%) were neither genotoxic nor carcinogenic, 4 (11.4%) were carcinogenic in at least one sex of mice or rats but tested negative in genotoxicity assays, 12 (34.3%) tested positive in at least one genotoxicity assay but were non-carcinogenic, and 8 (22,9%) gave a positive response in at least one genotoxicity assay and in at least one carcinogenicity assay. Only 22 (18.3%) of the 120 drugs considered have all data required by current guidelines for testing of pharmaceuticals, but a large fraction of them were developed and marketed prior the present regulatory climate.

Introduction

Non-steroidal anti-inflammatory drugs (NSAIDs) and opioid analgesics are pharmaceuticals used for pathological conditions that often require their long-term administration. NSAIDs are used for the relief of mild-to-moderate pain, and for chronic inflammatory disorders. Opioids, often in combination of non-opioid analgesics, are used for chronic treatment of more severe pain. Among the various adverse reactions that these drugs may cause, the occurrence of genotoxic and/or carcinogenic effects cannot be excluded. In order to assess the potential risk to humans of genotoxic and carcinogenic effects, the regulatory authorities of Europe, USA and Japan recommend that genotoxicity and carcinogenicity studies are performed before the application for marketing approval of pharmaceuticals. Current guidelines for genotoxicity testing of pharmaceuticals [1], [2], [3] indicate a standard test battery that consists of: (i) a test for gene mutation in bacteria, (ii) an in vitro test with cytogenetic evaluation of chromosomal damage with mammalian cells or an in vitro mammalian cells gene mutation assay, (iii) an in vivo test for chromosomal damage using rodent hematopoietic cells. Guidelines for carcinogenicity testing of pharmaceuticals [4], [5] indicate that long-term carcinogenicity studies in rodents should be performed for all pharmaceuticals whose expected clinical use is continuous for at least 6 months as well as for pharmaceuticals used frequently in an intermittent manner in the treatment of chronic recurrent conditions. In long-term carcinogenicity assays, the highest dose should be at least 25-fold higher, on a mg/m² basis, than the maximum recommended human daily dose or represent a 25-fold ratio of rodent to human AUC.

NSAIDs and opioids are extensively used. From the 2007 edition of the Martindale [6], it can be inferred that 109 drugs of these families are on the market, and majority of them are marketed in several countries. The International Agency for Research on Cancer [7] in the 91 volumes of IARC Monographs on the Evaluation of Carcinogenic Risks to Humans published in the years from 1972 to 2007 examined more than 200 drugs but these included only 7 analgesics and anti-inflammatory drugs: analgesics containing phenacetin, classified as carcinogenic to humans (Group 1); phenacetin, classified as probably carcinogenic to humans (Group 2 A); phenazopyridine, classified as possibly carcinogenic to humans (Group 2 B); aurothioglucose, oxyphenbutazone, paracetamol, and phenylbutazone, considered non-classifiable as to their carcinogenicity in humans (Group 3). In a review of Snyder and Green [8] on the genotoxicity of marketed pharmaceuticals, based on information obtained by the 1999 edition of the Physicians’ Desk Reference as well as from the peer-reviewed published literature, there are only 32 analgesics and anti-inflammatory drugs, but no data are reported for 11 of them and for some of the remaining information is quite limited. These premises indicate that in prescribing most analgesics and anti-inflammatory drugs the evaluation of the benefit/genotoxic–carcinogenic effects ratio is impossible. Therefore we deemed useful to examine whether data allowing a more complete information can be retrieved.

This review is a compendium of all the genotoxicity and carcinogenicity data that have been found in an extensive search. For each drug considered, the search terms were genotoxic activity and carcinogenic activity. The search was conducted primarily in peer-reviewed journals using Medline, Toxline, and the Registry of Toxic Effects of Chemicals Substances [9]. Additional unpublished data were obtained from Micromedex and from the following websites: http://www.toxnet.nlm.nih.gov, http://www.ntp.server.niehs.nih.gov, http://www.potency.berkeley.edu, http://www.fda.gov/cder, http://www.scirus.com, http://www.inchem.org, http://www.updateusa.com, http://www.osha.gov. Concerning data that are not published in peer-reviewed journals, in some cases the tests were conducted under the oversight of authoritative bodies, such as the U.S. National Toxicology Program; in the other cases the genotoxicity and carcinogenicity data are those reported by the Physician's Desk Reference [10] or in the final package insert approved by the Center for Drug Evaluation and Research of the Food and Drug Administration. Unfortunately, this additional unpublished information is often incomplete; in particular, the results of genotoxicity assays are usually reported without any information of the doses that have been tested. Moreover, often no information is given whether the in vitro genotoxicity assays were performed in both the presence and the absence of an exogenous metabolic system; in these cases, taking into account that this procedure is required by the guidelines, in the absence of a specific indication the result is reported in the tables as obtained in both these experimental conditions.