sildenafil-citrate and Chemical-and-Drug-Induced-Liver-Injury

Sildenafil citrate (Viagra®) is a vasoactive agent available worldwide since 1998 for the treatment of male erectile dysfunction. It is a selective phosphodiesterase type 5-enzyme inhibitor able to potentiate the downstream effects of nitric oxide on smooth muscle relaxation and vasodilation through its effects on the cyclic guanosine monophosphate (c-GMP) pathway in the erectile tissue of the penis. When sildenafil is orally administered, it is rapidly absorbed with a maximum plasma concentration achieved within 1 h and has a terminal half-life of between 3 to 6 h. The drug is extensively and rapidly metabolized by the liver, primarily by the CYP3A4 enzyme. Although the drug is well tolerated, specific adverse events have been observed, like flushing, headaches, dyspepsia, and visual disturbances. Liver toxicity related to sildenafil consumption has been considered a very rare event. However, in the last decade, some cases of sildenafil-associated hepatotoxicity have been reported. Furthermore, some hepatic intoxications have been reported after the intake of "natural" or "herbal" aphrodisiac supplements sold through Internet, sex shops, social media, and by word-of-mouth found to contain sildenafil and other phosphodiesterase type 5 (PDE-5) inhibitors. Studies investigating a possible link between sildenafil use and liver damage are limited, and the underlying mechanism responsible for hepatotoxicity is still missing. Studies in animals evidence that the hematopoietic function of the liver may have severely been affected as a result of a probable toxic effect of sildenafil. Here, the studies reporting liver toxicity by sildenafil in humans and in animals are reported and discussed.

Topics: Chemical and Drug Induced Liver Injury; Erectile Dysfunction; Humans; Male; Piperazines; Purines; Sildenafil Citrate; Sulfones; Urological Agents

Elevation of phosphodiesterase-5 (PDE5) activity converts cyclic guanosine monophosphate (cGMP) to 5'-GMP, a mechanism that could be associated with drug-mediated hepatotoxicity. This study investigated whether selective inhibition of PDE5 by sildenafil could offer protection against hepatotoxicity induced by carbon tetrachloride (CCl4).. CCl4 (0.5 mL/kg) was administered intraperitoneally to induce hepatotoxicity. The control group received normal saline. Sildenafil (5 mg, 10 mg, and 20 mg/kg, p.o.) was administered to CCl4-treated rats.. CCl4 significantly increased the serum levels of gamma glutamyl transferase (γ-GT), alkaline phosphatase (ALP), aspartate aminotransferase (AST), and alanine aminotransferase (ALT) and reduced total protein (TP) (p<0.05). Pretreatment with sildenafil moderately reduced ALP, AST, and ALT activities with modest increase in TP level. CCl4-induced changes in the antioxidant status of the liver were significantly improved by sildenafil, especially at the lowest dose of 5 mg/kg by elevating the levels of reduced glutathione (GSH), glutathione peroxidase (GPx), catalase (CAT), superoxide dismutase (SOD), and glutathione-S-transferase (GST) and preventing lipid peroxidation (p<0.05). Sildenafil did not significantly alter the total cholesterol and triglyceride levels. However, high-density lipoprotein (HDL) level was significantly increased by sildenafil (p<0.05).. The results from this study suggest that sildenafil, when used at low doses, may be a useful pharmacological protective agent against CCl4-induced hepatotoxicity.

Topics: Alanine Transaminase; Alkaline Phosphatase; Animals; Antioxidants; Aspartate Aminotransferases; Carbon Tetrachloride; Catalase; Chemical and Drug Induced Liver Injury; Cyclic Nucleotide Phosphodiesterases, Type 5; gamma-Glutamyltransferase; Glutathione; Lipid Peroxidation; Liver; Male; Oxidative Stress; Phosphodiesterase 5 Inhibitors; Protective Agents; Rats; Rats, Wistar; Sildenafil Citrate; Superoxide Dismutase

Detection of Phosphodiesterase Type 5 (PDE-5) inhibitors and their analogues in "100% natural" or "herbal" supplements have been described in numerous reports. However, few reports have been published in relation to actual harm caused by counterfeit erectile dysfunction herbal supplements. We describe a case of a 65-year old male admitted to a tertiary hospital with acute liver toxicity, possibly induced by adulterated "Chinese herbal" supplement "Tiger King" for sexual enhancement. Chemical analysis of the tablets discovered the presence of therapeutic doses of sildenafil with no other herbal components. Other medications were excluded as potential causes of the hepatic impairment. According to the Naranjo adverse drug reaction scale and the Roussel Uclaf Causality Assessment Method (RUCAM) the probability of association of Hepatotoxicity with Sildenafil was "possible" and "probable" respectively (Naranjo score of 4, RUCAM score of 7). Within three days of admission, the patient's clinical status and liver function improved without any specific treatment. His liver function tests normalized 30 days post discharge. Further pharmacovigilance actions should be taken by regulatory authorities and pharmaceutical companies in order to determine the relation between sildenafil and hepatotoxicity. This case emphasizes the importance of raising public awareness on the potential dangers of "Tiger king" in particular, and other counterfeit medications or herbal supplements of unknown origin.

Topics: Aged; Chemical and Drug Induced Liver Injury; Drugs, Chinese Herbal; Humans; Male; Phosphodiesterase 5 Inhibitors; Sildenafil Citrate

Sildenafil is used for the treatment of erectile dysfunction and is helping millions of men around the world to achieve and maintain a long lasting erection. Fifty healthy male rabbits (Oryctolagus cuniculus) were used in the present study and exposed daily to sildenafil (0, 1, 3, 6, 9 mg/kg) for 5 days per week for 7 weeks to investigate the biochemical changes and alterations in the hepatic tissues induced by this drug overdosing. In comparison with respective control rabbits, sildenafil overdoses elevated significantly (p-value<0.05, ANOVA test) alanine aminotransferase (ALT), aspartate aminotransferase (AST), testosterone, follicular stimulating hormone and total protein, while creatinine and urea were lowered with no significant alteration was observed in uric acid and luteinizing hormone concentration. Also sildenafil provoked hepatocytes nuclear alterations, necrosis, hydropic degeneration, bile duct hyperplasia, Kupffer cells hyperplasia, inflammatory cells infiltration, hepatic vessels congestion and evident partial depletion of glycogen content. The results show that subchronic exposure to sildenafil overdoses exhibits significant biochemical and alterations in the hepatic tissues that might affect the functions of the liver and other vital organs.

Topics: Animals; Bile Ducts; Biomarkers; Chemical and Drug Induced Liver Injury; Drug Overdose; Hyperplasia; Kupffer Cells; Liver; Liver Function Tests; Male; Necrosis; Phosphodiesterase 5 Inhibitors; Rabbits; Risk Assessment; Sildenafil Citrate; Time Factors; Toxicity Tests

The bile salt export pump (BSEP) is expressed at the canalicular domain of hepatocytes, where it serves as the primary route of elimination for monovalent bile acids (BAs) into the bile canaliculi. The most compelling evidence linking dysfunction in BA transport with liver injury in humans is found with carriers of mutations that render BSEP nonfunctional. Based on mounting evidence, there appears to be a strong association between drug-induced BSEP interference and liver injury in humans; however, causality has not been established. For this reason, drug-induced BSEP interference is best considered a susceptibility factor for liver injury as other host- or drug-related properties may contribute to the development of hepatotoxicity. To better understand the association between BSEP interference and liver injury in humans, over 600 marketed or withdrawn drugs were evaluated in BSEP expressing membrane vesicles. The example of a compound that failed during phase 1 human trials is also described, AMG 009. AMG 009 showed evidence of liver injury in humans that was not predicted by preclinical safety studies, and BSEP inhibition was implicated. For 109 of the drugs with some effect on in vitro BSEP function, clinical use, associations with hepatotoxicity, pharmacokinetic data, and other information were annotated. A steady state concentration (C(ss)) for each of these annotated drugs was estimated, and a ratio between this value and measured IC₅₀ potency values were calculated in an attempt to relate exposure to in vitro potencies. When factoring for exposure, 95% of the annotated compounds with a C(ss)/BSEP IC₅₀ ratio ≥ 0.1 were associated with some form of liver injury. We then investigated the relationship between clinical evidence of liver injury and effects to multidrug resistance-associated proteins (MRPs) believed to play a role in BA homeostasis. The effect of 600+ drugs on MRP2, MRP3, and MRP4 function was also evaluated in membrane vesicle assays. Drugs with a C(ss)/BSEP IC₅₀ ratio ≥ 0.1 and a C(ss)/MRP IC₅₀ ratio ≥ 0.1 had almost a 100% correlation with some evidence of liver injury in humans. These data suggest that integration of exposure data, and knowledge of an effect to not only BSEP but also one or more of the MRPs, is a useful tool for informing the potential for liver injury due to altered BA transport.

Topics: Animals; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 11; ATP-Binding Cassette Transporters; Biological Transport; Chemical and Drug Induced Liver Injury; Cluster Analysis; Drug-Related Side Effects and Adverse Reactions; Humans; Liver; Male; Multidrug Resistance-Associated Proteins; Pharmacokinetics; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Risk Assessment; Risk Factors; Toxicity Tests

Altered regulation of nitric oxide-cyclic guanosine monophosphate (NO-cGMP) is present in liver cirrhosis. Several experimental studies have shown that selective modulation of NO metabolism in the liver reduces intrahepatic resistance and portal pressure in cirrhosis. This preliminary study investigated whether selective inhibition of phosphodiesterase-5 (PDE-5), which prevents the conversion of cGMP to 5'-GMP, as well as non-selective inhibition of PDE isozymes could ameliorate hepatic toxicity induced by paracetamol (PCM).. PCM (250 mg/kg, i.p.) was administered to induce hepatotoxicity. Control rats received physiological saline (10 mL/kg, p.o.), while sildenafil (a selective PDE-5 inhibitor) and aminophylline (a non-selective PDE inhibitor) were administered separately at 10 mg/kg p.o. to PCM-treated rats.. PCM hepatotoxicity, characterized by elevation of aspartate and alanine aminotransferases, hepatic degeneration, and centrilobular necrosis, was attenuated by both PDE inhibitors. Sildenafil and aminophylline significantly (p<0.05) reduced plasma aspartate aminotransferase activity by 49.6% and 39.8%, respectively, with moderate increase in alanine aminotransferase activity by 26.1% and 20.4%, respectively, in PCM-treated rats. Decreases in total protein and albumin induced by PCM were significantly (p<0.05) prevented by 30.0% and 22.2%, respectively, following sildenafil administration, while aminophylline decreased these proteins by 14.0% and 25.9%, respectively. Sildenafil and aminophylline significantly (p<0.05) reduced lipid peroxidation by 30.7% and 19.7%, respectively, while moderately increasing glutathione (GSH) in the PCM-treated rats. Both drugs did not significantly alter the total cholesterol and triglyceride levels.. These preliminary data suggest that pharmacological inhibition of PDE isozymes may be a useful strategy in protecting against PCM hepatic toxicity.

Topics: Acetaminophen; Alanine Transaminase; Aminophylline; Animals; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Glutathione; Lipid Peroxidation; Male; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Piperazines; Purines; Rats; Rats, Wistar; Sildenafil Citrate; Sulfones

Topics: Chemical and Drug Induced Liver Injury; Contraindications; Endothelin A Receptor Antagonists; Familial Primary Pulmonary Hypertension; Fatal Outcome; Female; Humans; Hypertension, Pulmonary; Isoxazoles; Jaundice; Liver Failure, Acute; Piperazines; Purines; Sildenafil Citrate; Sulfones; Thiophenes; Vasodilator Agents; Young Adult

We describe a patient with a hepatotoxic reaction, presenting with general malaise, severe jaundice, and pruritus. This turned out to be caused by the, at first unrevealed, use of sildenafil. The injury seems to be hepatocanalicular, characterized by a hepatocellular liver test pattern, combined with extensive cholestasis on liver biopsy. One should bare in mind that the use of sildenafil may not be readily disclosed by the patient nor his doctor.

Topics: Chemical and Drug Induced Liver Injury; Cholestasis, Intrahepatic; Humans; Male; Middle Aged; Phosphodiesterase Inhibitors; Piperazines; Pruritus; Purines; Sildenafil Citrate; Sulfones; Truth Disclosure

Topics: Acute Disease; Chemical and Drug Induced Liver Injury; Humans; Male; Middle Aged; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones

Topics: Chemical and Drug Induced Liver Injury; Humans; Male; Middle Aged; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

The treatment of erectile dysfunction (ED) has been revolutionised by new agents to inhibit the enzyme PDE5. The scientific basis of this treatment of ED includes relaxation of the corpus cavernosum smooth muscle tissue by inhibition of PDE5 that breaks down cGMP, the key pathway for the production of erectile function in humans. Many clinical studies, both pre- and post-marketing, have demonstrated the clinical efficacy and safety of sildenafil (Viagra, Pfizer) - the first approved selective PDE inhibitor for the treatment of ED. Sildenafil is inhibitory of PDE5 at a rate tenfold higher than for the next PDE (PDE6), which produces visual changes through the retinal rods. Its clinical effectiveness has been well documented in the majority of men with ED irrespective of aetiology. The aetiology of ED, also, does not appear to effect the function of sildenafil in relaxing corpus cavernosum smooth muscle tissue. Adverse events are usually associated with the vascular changes from PDE5 inhibition. These include headache and flushing. Each of these adverse events, however, declines with medication use. With the use of sildenafil, it has been clearly, clinically demonstrated that the selective inhibition of PDE5 is an appropriate, effective, safe method for the treatment of ED of all aetiologies and severities.

Topics: Aged; Area Under Curve; Central Nervous System Diseases; Chemical and Drug Induced Liver Injury; Chronic Disease; Erectile Dysfunction; Humans; Kidney Diseases; Male; Phosphodiesterase Inhibitors; Piperazines; Product Surveillance, Postmarketing; Purines; Sildenafil Citrate; Sulfones

Topics: Acute Disease; Aged; Chemical and Drug Induced Liver Injury; Diabetes Mellitus, Type 2; Erectile Dysfunction; Humans; Hypercholesterolemia; Hypertension; Male; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents