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Prothionamide
Tuberculosis (2008) 88(2) 139–140
Prothionamide Generic and additional names: Prothionamide; 2-propylthioisonicotinamide; S NH 2 prothionamide; 2-propyl-4-thiocarbamoylpyridine CAS name: 2-Propyl-4-pyridinecarbothioamide CAS registry #: 14222-60-7 Molecular formula: C9 H12 N2 S N Me Molecular weight: 180.27 Intellectual property rights: Generic Derivatives: Prothionamide is the propyl analog of ethionamide Solubility: Soluble in ethanol, methanol; slightly soluble in ether, chloroform; practically insoluble in water [Merck Index]. Formulation and optimal human dosage: 250 g tablet, 500 750 mg daily Basic biology information Drug target/mechanism: Prothionamide (PRO), see ethionamide (ETA). Drug resistance mechanism: There is complete crossresistance between PRO and ETA, and resistance emerges rapidly.1 In-vitro potency against MTB: MIC Mycobacterium tuberculosis H37Rv: ~0.5 mg/ml.2 Spectrum of activity: PRO has activity against mycobacterial species including M. leprae and M. avium.2 PRO killed M. leprae more quickly than did ETA.3 Other in-vitro activity: See ETA. ETA and PRO are bactericidal.2 In-vivo efficacy in animal model: PRO is as active as ETA against M. tuberculosis in mice.4 See also ETA. Efficacy in humans PRO is used interchangeably with ETA according to Wang et al.2 In a clinical trial with leprosy patients PRO (250 or 500 mg/day) outperformed ETA at the same dose.3 PRO has been reported as better tolerated than ETA in humans.4 ADME data See table 1 for main PK characteristics. Other ADME data: • Human: PRO, like ETA, is rapidly eliminated, with the half-life for PRO being slightly less than for ETA. Plasma concentrations for PRO are less than for ETA.4
Human metabolic pathway: Conversion to the active sulfoxide metabolite takes place with PRO and ETA; the sulfoxides are then metabolized to the nicotinamide and nicotinic acid forms, both of which have no anti-bacterial activity. Other metabolites such as N-methylation and oxidation of the pyridine ring are also formed. Of the total dose given, 0.16% is excreted as PRO and 1.2% excreted as PRO sulfoxide; less than 0.1% is excreted unchanged in the faeces.4 Safety and Tolerability Animal toxicity: LD50 in mice, rats (g/kg): 1.0, 1.32 orally [Merck Index]. Human drug drug interactions: Hepatotoxicity is considerably increased when PRO is used in combination therapy with rifampicin and thiacetazone.5 Human potential toxicity: PRO has been described as more toxic1 or less toxic4 than ETA. PRO should be avoided during pregnancy or in women of childbearing potential unless the benefits outweigh its possible hazards.5 Human adverse reactions: Most common adverse reactions are dose-related gastrointestinal disturbances, anorexia, excessive salivation, a metallic taste, nausea, vomiting, abdominal pain and diarrhoea. CNS disturbances include depression, anxiety, psychosis, headache, postural hypotension and asthenia. Peripheral and optic neuropathy and pellagra-like syndrome have occurred. Hepatitis may occur especially when given in association with rifampicin.
1472-9792/$ - see front matter © 2008 TB Alliance. Published by Elsevier Ltd. All rights reserved.
PRO
140
Prothionamide
Table 1 Species
Half-life (h)
Human
1.38
AUC (mg·h/l)
Cmax (mg/ml)
Volume distribution (l/kg)
Other side effects include hypersensitivity reactions, alopecia, dermatitis, endocrine disturbances, hypoglycaemia, and hypothyroidism with or without goiter.5
References 1. Di Perri G, Bonora S (2004) Which agents should we use for the treatment of multidrug-resistant Mycobacterium tuberculosis?J Antimicrob Chemother 54, 593 602.
Clearance (ml/h)
PK methodology
250 mg dose in humans. Cmax for ETA is about 1.8 times higher than for PRO, with the same ratios being observed for the sulfoxide metabolites.4
2. Wang F, et al. (2007) Mechanism of thioamide drug action against tuberculosis and leprosy. J Exp Med 204, 73 8. 3. Fajardo T, et al. (2006) A clinical trial of ethionamide and prothionamide for treatment of lepromatous leprosy. Am J Trop Med Hyg 74, 457 61. 4. Jenner P, et al. (1984) A comparison of the blood levels and urinary excretion of ethionamide and prothionamide in man. J Antimicrob Chemother 13, 267 77. 5. www.promedgroup.com/prothionamide
Prothionamide Generic and additional names: Prothionamide; 2-propylthioisonicotinamide; S NH 2 prothionamide; 2-propyl-4-thiocarbamoylpyridine CAS name: 2-Propyl-4-pyridinecarbothioamide CAS registry #: 14222-60-7 Molecular formula: C9 H12 N2 S N Me Molecular weight: 180.27 Intellectual property rights: Generic Derivatives: Prothionamide is the propyl analog of ethionamide Solubility: Soluble in ethanol, methanol; slightly soluble in ether, chloroform; practically insoluble in water [Merck Index]. Formulation and optimal human dosage: 250 g tablet, 500 750 mg daily Basic biology information Drug target/mechanism: Prothionamide (PRO), see ethionamide (ETA). Drug resistance mechanism: There is complete crossresistance between PRO and ETA, and resistance emerges rapidly.1 In-vitro potency against MTB: MIC Mycobacterium tuberculosis H37Rv: ~0.5 mg/ml.2 Spectrum of activity: PRO has activity against mycobacterial species including M. leprae and M. avium.2 PRO killed M. leprae more quickly than did ETA.3 Other in-vitro activity: See ETA. ETA and PRO are bactericidal.2 In-vivo efficacy in animal model: PRO is as active as ETA against M. tuberculosis in mice.4 See also ETA. Efficacy in humans PRO is used interchangeably with ETA according to Wang et al.2 In a clinical trial with leprosy patients PRO (250 or 500 mg/day) outperformed ETA at the same dose.3 PRO has been reported as better tolerated than ETA in humans.4 ADME data See table 1 for main PK characteristics. Other ADME data: • Human: PRO, like ETA, is rapidly eliminated, with the half-life for PRO being slightly less than for ETA. Plasma concentrations for PRO are less than for ETA.4
Human metabolic pathway: Conversion to the active sulfoxide metabolite takes place with PRO and ETA; the sulfoxides are then metabolized to the nicotinamide and nicotinic acid forms, both of which have no anti-bacterial activity. Other metabolites such as N-methylation and oxidation of the pyridine ring are also formed. Of the total dose given, 0.16% is excreted as PRO and 1.2% excreted as PRO sulfoxide; less than 0.1% is excreted unchanged in the faeces.4 Safety and Tolerability Animal toxicity: LD50 in mice, rats (g/kg): 1.0, 1.32 orally [Merck Index]. Human drug drug interactions: Hepatotoxicity is considerably increased when PRO is used in combination therapy with rifampicin and thiacetazone.5 Human potential toxicity: PRO has been described as more toxic1 or less toxic4 than ETA. PRO should be avoided during pregnancy or in women of childbearing potential unless the benefits outweigh its possible hazards.5 Human adverse reactions: Most common adverse reactions are dose-related gastrointestinal disturbances, anorexia, excessive salivation, a metallic taste, nausea, vomiting, abdominal pain and diarrhoea. CNS disturbances include depression, anxiety, psychosis, headache, postural hypotension and asthenia. Peripheral and optic neuropathy and pellagra-like syndrome have occurred. Hepatitis may occur especially when given in association with rifampicin.
1472-9792/$ - see front matter © 2008 TB Alliance. Published by Elsevier Ltd. All rights reserved.
PRO
140
Prothionamide
Table 1 Species
Half-life (h)
Human
1.38
AUC (mg·h/l)
Cmax (mg/ml)
Volume distribution (l/kg)
Other side effects include hypersensitivity reactions, alopecia, dermatitis, endocrine disturbances, hypoglycaemia, and hypothyroidism with or without goiter.5
References 1. Di Perri G, Bonora S (2004) Which agents should we use for the treatment of multidrug-resistant Mycobacterium tuberculosis?J Antimicrob Chemother 54, 593 602.
Clearance (ml/h)
PK methodology
250 mg dose in humans. Cmax for ETA is about 1.8 times higher than for PRO, with the same ratios being observed for the sulfoxide metabolites.4
2. Wang F, et al. (2007) Mechanism of thioamide drug action against tuberculosis and leprosy. J Exp Med 204, 73 8. 3. Fajardo T, et al. (2006) A clinical trial of ethionamide and prothionamide for treatment of lepromatous leprosy. Am J Trop Med Hyg 74, 457 61. 4. Jenner P, et al. (1984) A comparison of the blood levels and urinary excretion of ethionamide and prothionamide in man. J Antimicrob Chemother 13, 267 77. 5. www.promedgroup.com/prothionamide