Cytochrome P450 and the Clinical Implications ... or inducer and the metabolism of which is not readily inhibited by other drugs. Cytochrome P450 (often abbreviated "CYP") is a class of enzymes that is involved in the metabolism of many medications Cytochrome P450 enzymes are located primarily in the liver Cytochrome P450 enzymes are subdivided into classes (e.g. Quinidine: the renal and non ... Co-administration of mexiletine with a hepatic enzyme inducer (CYP1A2 inducer: omeprazole; CYP2D6 inducer: phenytoin, rifampicin) may increase the clearance and elimination rate of mexiletine due to an increased hepatic metabolism, resulting in decreased plasmatic concentrations and half-life of mexiletine. Physiologic processes that generally reduce hepatic metabolism and renal clearance increase serum quinidine levels, while comedication with cytochrome p450 (CYP)-enzyme inducers enhances clearance and results in lower blood concentrations. Cytochrome P450 enzymes are essential to metabolise many medications. AUC: area under the concentration-time curve; CYP: cytochrome P450; DDI: drug-drug interaction; OATP1B1: organic anion transporting polypeptide 1B1; OAT3: organic anion transporter 3; P-gp: P-glycoprotein. Although this class has more than 50 enzymes, six of them metabolize 90 percent of drugs, with the two most significant enzymes being CYP3A4 and CYP2D6. Note: Index inducers predictably induce metabolism via a given pathway and are commonly used in prospective clinical DDI studies. The half-life of quinidine is 6 to 8 hours. Enzyme Inducer. INTRO The cytochrome P450 is a superfamily of mono- oxygenases Heme-containing enzymes OR hemoproteins Officially abbreviated as CYP Is a large and diverse group of enzymes that catalyze the oxidation of organic substances They absorb light at a wavelength of 450 nm The kinetics of formation of dihydromorphine in both groups were best described by a single enzyme Michaelis-Menten model although inhibition studies in extensive metabolizers suggested involvement of two enzymes with similar K(m) values. Just because a medication interacts with one substrate of a particular cytochrome P450 pathway, does not mean it affects all … of the main guidance documents for details. This is because numerous medications, nutrients, and herbal therapies are metabolized through the cytochrome P450 (CYP450) enzyme system. (c)Listed based on pharmacogenetic studies. (l) Selective substrate of OATP1B3 (vs. OATP1B1). Abbreviations: (2010), Hum Genomics, 5(1):61]. Using inhibition by the quinidine/quinine isomer pair as a marker for the activity of cytochrome P450-SP/DB, the role of this enzyme in the in vitro oxidation of the enantiomers of metoprolol by human liver microsomes was examined. Conversely, in another case quinidine inhibited the metabolism of pentobarbital [125]. Potentially Toxic Concentration >40 mg/L. Latterly, the importance of the system in metabolising drugs has been recognised. This table is prepared to provide examples of in vitro substrates for various transporters and not intended to be an exhaustive list. BCRP: (1) AUC fold-increase of sulfasalazine ≥1.5 with co-administration and (2) in vitro inhibitor. 2D6, 3A4, 2C8, etc.) Moderate sensitive substrates are drug that demonstrate an increase in AUC of ≥2 to <5-fold with strong index inhibitors of a given metabolic pathway in clinical DDI studies. Cytochrome P450 enzymes are located primarily in the liver; Cytochrome P450 enzymes are subdivided into classes (e.g. Pentobarbital increases the clearances and reduces the plasma concentrations of some beta-blockers, such as alprenolol [100,101], with loss of beta-blockade. Essential for the production of cholesterol, steroids, prostacyclins, and thromboxane A 2, cytochrome Ps (CYPs) are the major enzymes involved in drug metabolism, accounting for approximately 75% of the total metabolism of all drugs . Table 1-3. (a) Strong inhibitor of CYP1A2 and CYP2C19, and moderate inhibitor of CYP2D6 and CYP3A. Rifampin induces the P450 enzymes responsible for metabolizing oral contraceptives and immunosuppressant drugs. Cytochrome P450 3A4 (abbreviated CYP3A4) (EC 1.14.13.97) is an important enzyme in the body, mainly found in the liver and in the intestine. * Time-dependent inhibitors. Oxcarbazepine reduces serum felodipine concentrations, although less than carbamazepine does [60]. Table 5-2: Examples of clinical inhibitors for transporters (for use in clinical DDI studies and drug labeling) (9/26/2016). The CYP3A inducer, α-naphthoflavone, increased N-demethylation rates. The half-lif… Drs. As a potent P450 enzyme inducer, rifampin is associated with drug interactions of substantial clinical significance. BCRP: (1) AUC fold-increase≥2 with pharmacogenetic alteration of ABCG2 (421C>A) and (2) in vitro transport by BCRP expression systems. Inducers increase CYP450 enzyme activity by increasing enzyme synthesis. (b) Also OATP1B1 substrate. Strong and moderate index inducers are drugs that decreases the AUC of sensitive index substrates of a given metabolic pathway by ≥80% and ≥50% to <80%, respectively. Classification And Nomenclature of Cytochrome P450. Cytochrome P450 (often abbreviated "CYP") is a class of enzymes that is involved in the metabolism of many medications Cytochrome P450 enzymes are located primarily in the liver Cytochrome P450 enzymes are subdivided into classes (e.g. OCT2/MATE: Well-established substrate of cationic transport system (metformin). (n) Also a substrate of OAT1. The end result of these drug interactions could be an unplanned pregnancy or immune rejection in a transplant patient. CYTOCHROME P450 ENZYMES Presented By Deshmukh Md Faizan M. Pharm (1st Sem) DEPARTMENT OF PHARMACEUTICAL CHEMISTRY, R.C.PATEL INSTITUTE OF PHARMACEUTICAL EDUCATION AND RESEARCH, SHIRPUR 1 2. The active site of cytochrome P450 contains a heme center. Nutrition also plays an important role in maintaining xenobiotic-metabolizing enzymes and their cofactors (Parke and Ioannides 1981). Catalytic Cycle of Cytochrome P450. CYP2D6 is primarily expressed in the liver.It is also highly expressed in areas of the central nervous system, including the substantia nigra.. CYP2D6, a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. Oxcarbazepine is a weaker enzyme inducer than carbamazepine. Update: clinically significant cytochrome P450 drug interaction. (a)Most of P-gp inhibitors also inhibit CYP3A. Increases in theophylline clearance have been reported during co-administration of pentobarbital [130,131] and secobarbital [132]. Certain drugs are known to be P450 inhibitors, but some foods can inhibit these enzymes too. Table 1-2: Examples of in vitro selective inhibitors for P450-mediated metabolism (9/26/2016). Note:(a)Inhibitor of MRP2, BCRP, NTCP and OATPs. The cytochrome P450 system performs this function by oxidising, hydrolysing or reducing the chemicals. (a) Strong inducer of CYP3A and moderate inducer of CYP1A2, CYP2C19. (2010), Hum Genomics, 5(1):61]. (2010), Hum Genomics, 5(1):61], and the list of references is available here. (2010), Hum Genomics, 5(1):61]. DDI data were collected based on a search of the University of Washington Metabolism and Transport Drug Interaction Database [Hachad et al. Moderate sensitive substrates are drugs that demonstrate an increase in AUC of ≥2 to <5-fold with strong index inhibitors of a given metabolic pathway in clinical DDI studies. ALISON L. JONES BSc, MD, PAUL I. DARGAN MBBS, MD, in Haddad and Winchester's Clinical Management of Poisoning and Drug Overdose (Fourth Edition), 2007. In six healthy subjects pentobarbital 100 mg reduced the plasma concentrations of steady-state oral alprenolol 200 mg/day for 10 days and its metabolite 4-hydroxyalprenolol, without changes in half-lives [102]. (2010), Hum Genomics, 5(1):61)], and the list of references is available here. Pharmacist’s Letter 1999 Document No.:150400. Otton SV(1), Crewe HK, Lennard MS, Tucker GT, Woods HF. Note: J. Biol. In a placebo-controlled study in healthy women, oxcarbazepine 900 mg/day reduced the serum concentrations of ethinylestradiol and levonorgestrel by about 50% [61]. Cyclosporine A and eltrombopag were also included, although the available DDI information was with rosuvastatin, where inhibition of both BCRP and OATPs may have contributed to the observed interaction. Ethacizine prolonged the half-life of moracizine by increasing its volume of distribution without a change in clearance. This substance has appropriate characteristics of a marker drug. While many drugs are deactivated by CYP3A4, there are also some drugs which are activated by the enzyme. In a retrospective study, in which 376 samples from 222 patients were analysed, oxcarbazepine induced the metabolism of lamotrigine and reduced lamotrigine concentrations by about 29% [62]. (h) The Ki value is estimated to be lower in inhibition studies. (i) Also an inhibitor of OAT3. based on their structure ; Drug metabolism; Drugs may be metabolized by one subclass of CYP enzyme (ex. Index inducers listed in this table were selected based on potency of induction, safety profiles, and number of reported clinical DDI studies with different in vivo substrates (≥ 2 substrates). They have been several reports of interactions in which barbiturates induce the metabolism of coumarin anticoagulants. AUC: area under the concentration-time curve; CYP: cytochrome P450; DDI: drug-drug interaction; EM: extensive metabolizer; OATP1B1: organic anion transporting polypeptide 1B1. There was a significant correlation between methadone oral availability and intestinal availability, since only rifampicin altered oral methadone availability. Learn cytochrome p450 with free interactive flashcards. Phenytoin is metabolized to a 3,4-epoxide.160 An autoantibody against a 53-kD microsomal protein has been reported.158 Hepatitis is predominantly hepatocellular, but sometimes it is mixed. A similar course of events occurred in a 73-year-old woman taking acenocoumarol who needed a six-fold increase in dose after the introduction of rifampicin [438]. * Note: Index substrates predictably exhibit exposure increase due to inhibition or induction of a given metabolic pathway and are commonly used in prospective clinical DDI studies. Treatment of rats with loratadine caused a 1.4- to 2.0-fold increase in the 2 beta-, 6 beta- and 15 beta-hydroxylation of testosterone, which was associated with a similar increase in the levels of immunoreactive P450 3A1 and/or 3A2. Metoprolol is a cardioselective beta-blocker that is used mainly in the treatment of arterial hypertension (Hansson et al., 1999), heart failure (MERIT-HF Study Group, 1999), and myocardial infarction (Chen et al., 2005). She developed weakness, hand tremor, lethargy, and asterixis after 3 weeks and electroencephalography showed typical triphasic waves. (a) We currently do not have sensitive index substrates for CYP2B6. 10–40 µg/mL. (d) Weak inducer of CYP2B6, CYP2C9, and CYP2C19. Table 4-2: Examples of in vitro inhibitors for transporters (9/26/2016). Measurement of product formation catalyzed by a panel of cDNA-expressed P450 isoforms revealed that maximal rates of CDE formation occurred with P450 2A6, followed by P450 3A4. Michalets EL. Valproic acid-induced hyperammonemic encephalopathy developed exclusively during concomitant treatment with lamotrigine + valproate in a psychiatric setting [174A]. (m) Also a substrate of OATP1B1. Since rifampicin is a powerful enzyme inducer, doses of coumarin anticoagulants may need to be increased markedly during co-administration, as has been reported again, in a 79-year-old man, in whom a 5- to 6-fold increase in warfarin dose was required to maintain an INR in the target range; after rifampicin was withdrawn the dose of warfarin was gradually reduced over the next 2 months [437]. Poland, A., E. Glover, F.H. (g) Strong inhibitors of CYP2C19 and CYP2D6. The end result of these drug interactions could be an unplanned pregnancy or immune rejection in a transplant patient. Phenytoin is a microsomal enzyme inducer. (d) Strong inhibitor of CYP2C8 and inhibitor of OATP1B1 and OAT3. 10–40 mg/L. The pharmacokinetics of the two drugs when given separately and together in single doses have been studied in eight healthy subjects [15]. Abbreviations: Cytochrome P450 enzymes in hepatocytes attached to SER ... CYP Inducer ↑Substrate concentration ↓Substrate concentration ↑Toxicity ↓Efficacy. the enzyme primarily responsible for metabo-lizing morphine, oxymorphone, tapentadol, and hydromorphone. (b) Strong inducer of CYP3A and moderate inducer of CYP1A2, CYP2C19. The Human Genome Project has identified 57 human genes coding for the various cytochrome P450 enzymes. based on their structure Cytochrome P450 Drug Interactions Lead authors: Terri L. Levien, R.Ph., and Danial E. Baker, Pharm.D., FASCP, FASHP (Last Updated May 2003-See newly added CYP2C8 category on page 4) The characterization of drug interactions by metabolic pathways is complex. Cruciferous vegetables and charcoal-broiled meats contain potent enzyme inducers, and diets containing these foods have been shown to modulate the biological effects of xenobiotics (Conney et al. This leads to an increase in the first-pass metabolism of quinidine, and thus increased requirements of oral quinidine. (c) Moderate sensitive substrates. (i) Based on effect of 200 mg/day modafinil. From: Handbook of Clinical Neurology, 2012, Gaetano Zaccara, Luciana Tramacere, in Side Effects of Drugs Annual, 2011. >40 µg/mL. BY DR. SRIRAM.R CYP 450 SYSTEM 2. Cytochrome p450 is a superfamily of membrane-bound hemoprotein isozymes with distinct classifications. For example, a patient taking the potent CYP3A4 inducer rifampin may have a roughly 90% reduction in serum concen- trations of CYP3A4 substrates, such as buspirone, triazolam, and verapamil. Table 5-1: Examples of clinical substrates for transporters (for use in clinical DDI studies and/or drug labeling) (12/03/2019). 10–40 µg/mL. (d)in vitro data suggested higher contribution of OAT3 than OAT1. For the interaction of carbonic anhydrase inhibitors with amobarbital, see above under Nervous system. DDI data were collected based on a search of the University of Washington Metabolism and Transport Drug Interaction Database [Hachad et al. Enzyme-inducing anticonvulsants cause a modest reduction in monohydroxycarbazepine concentrations [57]. (e) Strong inhibitor of CYP2C19 and moderate inhibitor of CYP2C9 and CYP3A. Therapeutic Range. Barbiturates are enzyme inducers [98]. (d) S-lansoprazole is a sensitive substrate in CYP2C19 EM subjects. This table is prepared to provide examples of clinical index inhibitors and is not intended to be an exhaustive list. based on their structure; Drug metabolism ; Drugs may be metabolized by one subclass of CYP enzyme (ex. Studies have shown that it can be classified as a “strong CYP3A inhibitor” when a certain preparation was used (e.g., high dose, double strength) or as a “moderate CYP3A inhibitor” when another preparation was used (e.g., low dose, single strength). Br J Clin Pharmacol 1997; 44: 549–555 Characterization of the human cytochrome P450 enzymes involved in the metabolism of dihydrocodeine L. C. Kirkwood,1 R. L. Nation1 & A. This table is prepared to provide examples of clinical index inducers and not intended to be an exhaustive list. Cytochrome P450 2D6 Known Drug Interaction Chart Drugs Metabolized by CYP2D6 Enzyme Drug Inhibitors of CYP2D6 Enzyme ANALGESICS CHOLINESTERASE INHIBITORS STRONG INHIBITORS OTHER KNOWN INHIBITORS:* codeine donepezil bupropion ANALGESICS hydrocodone cinacalcet celecoxib oxycodone COUGH SUPPRESSANT fluoxetine methadone phenacetin dextromethorphan paroxetine tramadol quinidine … It oxidizes small foreign organic molecules (xenobiotics), such as toxins or drugs, so that they can be removed from the body.. (g) Acid form is an OATP1B1 substrate, Table 3-2: Examples of clinical inhibitors for P450-mediated metabolisms (for concomitant use clinical DDI studies and/or drug labeling) (03/06/2020). (c)In vitro data suggested higher contribution of OAT1 than OAT3. Table 4-1: Examples of in vitro substrates for transporters (9/26/2016). (b)In vivo data suggested specific inhibition of OAT1. Phenobarbital is a potent cytochrome P450 enzyme inducer, leading to interactions with other drugs by increasing their clearance. Therapeutic Range. (g) Strong inducer of CYP3A and moderate inducer of CYP2C9, and CYP2C19. Summary. (2010), Hum Genomics, 5(1):61], and the list of references is available here. Cytochrome P450 2D6 (CYP2D6) is an enzyme that in humans is encoded by the CYP2D6 gene. The combination of moracizine with another antidysrhythmic drug ethacizine, in the weight ratio of 6:1, has been marketed in Russia under the name of metacizine (Ethmocor®). Location. Cytochrome P450 enzymes also function to metabolize potentially toxic compounds, including drugs and products of endogenous metabolism such as bilirubin, principally in the liver. Cytochrome P450 (CYP450) enzymes are essential for : Synthesis of cholesterol, steroids, prostacyclins, and TX A2. Metronidazole inhibits the metabolism of butobarbitone [121]. DDI data were collected based on a search of the University of Washington Metabolism and Transport Drug Interaction Database [Hachad et al. Unlike metabolic inhibition, there is usually a delay before enzyme activity increases, depending on the half-life of the inducing drug. P-gp: (1) AUC fold-increase≥2 with verapamil or quinidine co-administration and (2) in vitro transport by P-gp expression systems, but not extensively metabolized. Its administration to patients commonly causes a rise in γ-glutamyltransferase and may cause a small rise in ALT and AP in some patients.158 Clinical hepatitis is much less common (serious idiosyncratic reactions occur in approximately 1% of patients159) and occurs within 6 weeks of therapy, usually associated with fever, rash, lymphadenopathy, lymphocytosis, hepatomegaly, splenomegaly, and eosinophilia, suggesting an allergic mechanism. (d) Strong inhibitor of CYP2C19 and CYP3A, and weak inhibitor of CYP2B6. (f) Strong inhibitors of CYP2C19 and CYP2D6. Components. (f) Strong inhibitor of CYP2C19 and moderate inhibitor of CYP2C9 and CYP3A. Ethanol is known to induce certain cytochrome P450 (CYP) enzymes, particularly the 2E1 isoform, which has been shown to metabolise arachidonic acid (AA) to the 19-hydroxy metabolite (19-HETE), which could have pro-hypertensive activity; CYP4A, by comparison, is the principal AA omega-hydroxylase in the liver. (b) Also a substrate of OATPs. (c) Strong inhibitor of CYP2C8, weak inhibitor of CYP2B6, and inhibitor of OATP1B1. CYP450 enzymes can be inhibited or induced by some drugs, resulting in significant drug interactions that can cause unanticipated adverse reactions or therapeutic failures. The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely. A basic knowledge of cytochrome p450 enzymes helps to understand many drug interactions. of the main clinical DDI guidance document for details. It oxidizes small foreign organic molecules (xenobiotics), such as toxins or drugs, so that they can be removed from the body.. Note: Index inhibitors predictably inhibit metabolism via a given pathway and are commonly used in prospective clinical DDI studies. The .gov means it’s official.Federal government websites often end in .gov or .mil. Click to see full answer. Before sharing sensitive information, make sure you're on a federal government site. PubMed Google Scholar. Mechanistically, it is known that the reactive aflatoxin epoxide binds to the N7 position of guanines. Abbreviations: (h) The effect of St. John’s wort varies widely and is preparation-dependent. The glucoronide metabolite is also an inhibitor for CYP2C8 and OATP1B1. (l) The classification is based on studies conducted with intravenously administered conivaptan. (g) Selective substrate of OATP1B3 (vs. Moracizine prolonged the half-life of ethacizine by reducing its clearance despite a parallel reduction in volume. Recently, a single nucleotide polymorphism identified at position 734 of the CYP1A2 gene, was reported to affect … AUC: area under the concentration-time curve; CYP: cytochrome P450; DDI: drug-drug interaction. (f) Also an inhibitor of OATPs. When it is substituted for carbamazepine, plasma concentrations of concomitant drugs, such as valproate and neuroleptic drugs, can rise, owing to de-induction, leading to potential toxicity [57,58]. This table is prepared to provide examples of in vitro inhibitors for various transporters and not intended to be an exhaustive list. Cytochrome P450 (CYP) enzymes are a group of hem‐containing enzymes playing a key role in the metabolism of a variety of chemically diverse compounds, including pharmaceutical agents, xenobiotics, and endogenous compounds. ScienceDirect ® is a registered trademark of Elsevier B.V. ScienceDirect ® is a registered trademark of Elsevier B.V. A worldwide yearly survey of new data in adverse drug reactions, Meyler's Side Effects of Drugs (Sixteenth Edition), Haddad and Winchester's Clinical Management of Poisoning and Drug Overdose (Fourth Edition), Various dietary constituents possess biological activity as. (j) Also a substrate of BCRP. PubMed Google Scholar. In a randomized four-way crossover study in healthy subjects, the effects of intravenous and oral methadone were measured after pre-treatment with rifampicin (hepatic/intestinal CYP3A induction), troleandomycin (hepatic/intestinal CYP3A inhibition), grapefruit juice (selective intestinal CYP3A inhibition), or nothing [135]. In 12 healthy men there was a significant reduction in the AUC of phenazone after oral administration, and this was accompanied by an increase in oral phenazone clearance. **No selective inhibitor is available in vitro for CYP2C19- and CYP2B6-mediated metabolisms. See section IV.A.2. (c) Also a substrate of MRP2. >40 µg/mL. Use of quinidine inhibition to define the role of the sparteine/debrisoquine cytochrome P450 in metoprolol oxidation by human liver microsomes. The cytochrome P450 enzyme system is one of several metabolic systems which evolved to enable organisms to deal with lipid-soluble environmental chemicals. Note: Strong, moderate, and weak inducers are drugs that decreases the AUC of sensitive index substrates of a given metabolic pathway by ≥80%, ≥50% to <80%, and ≥20% to <50%, respectively. Oxcarbazepine metabolism is unaffected by several inhibitors of carbamazepine metabolism. Cell 31, 275–284. In the same individuals, the kinetics of moracizine after several days of therapy suggested possible autoinduction, with a significant reduction in AUC and an increase in oral clearance. (e) Strong inhibitor of CYP2C8 and inhibitor of OATP1B1 and OAT3. INHIBITORS, INDUCERS AND SUBSTRATES OF CYTOCHROME P450 ISOZYMES remember inhibitors and substrates INCREASE the effectiveness of another drug metabolized by that isozyme ... quinidine quinine repaglinide refabutin ritonavir saquinavir sertraline sibutamine sildenafil simvastatin sirolimus sufentanil tacrolimus tamoxifen testosterone Abbreviations: (g) Also an inhibitor of P-gp. DDI data were collected based on a search of the University of Washington Metabolism and Transport Drug Interaction Database [Hachad et al. OAT1/OAT3: (1) AUC fold-increase≥1.5 with probenecid co-administration, (2) fraction excreted unchanged into urine as an unchanged drug ≥ 0.5, and (3) in vitro transport by OAT1 or OAT3 expression systems. Table 2-3: Examples of clinical index inducers for P450-mediated metabolisms (for use in index clinical DDI studies) (9/26/2016). P-gp: (1) AUC fold-increase of digoxin ≥2 with co-administration and (2) in vitro inhibitor. i="">. Guideline on the Investigation of Drug Interactions. These enzymes are expressed in most tissues, with the highest abundance and largest number of individual CYP isoforms present in the liver. Levien TL., Baker DE. Pharmocotherapy 1998,18(1):84-112. While many drugs are deactivated by CYP3A4, there are also some drugs which are activated by the enzyme. This table is prepared to provide examples of clinical sensitive or moderate sensitive index substrates and is not intended to be an exhaustive list. Table 3-3: Examples of clinical inducers for P450-mediated metabolisms (for concomitant use clinical DDI studies and/or drug labeling) (12/03/2019). The cytochrome P450 enzymes may be inhibited by a variety of mechanisms [9, 12, 13] such as simple competition for substrates for cytochrome P450 (quinidine, sulfaphenazole), compounds that bind to the haem (cimetidine), compounds whose oxidation products bind to haem (troleandomycin) and direct irreversible inactivation (disulphiram). Enzyme inducers reduce the effects of drugs metabolized through this pathway, whereas enzyme inhibitors will result in increased drug levels. CYP3A4 is the most important of the CYP450 enzymes for drug metabolism and for drug interactions. Side Effects. DDI data were collected based on a search of the University of Washington Metabolism and Transport Drug Interaction Database [Hachad et al. Moracizine is an enzyme inducer and increases the rate of clearance of phenazone [85]. Drug interaction guideline for drug development and labeling recommendations (Draft, in Japanese). Detoxification of foreign chemicals Metabolism of drugs While present in most tissues of the body, CYP enzymes predominantly occupy the liver, intestines, and kidneys with its highest concentration in the liver.
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