α2-receptor

Lofexidine is one therapeutic option used for treating the onslaught of sympathetic outflow that typically commences upon induction of opiate withdrawal. It was approved for opiate detoxification in the UK, most of EU, and a select few countries worldwide during the 1980s and the 90s. Within the US and Canada, however, it remains an experimental drug[1].

Lofexidine is an alpha(2)-agonist structurally related to clonidine. It is not an effective antihypertensive agent; however, it decreases the sympathetic outflow responsible for many opioid withdrawal symptoms. Nine clinical studies were reviewed representing 354 patients receiving lofexidine including a recent Phase 3 clinical trial. Eight studies involved comparisons of lofexidine to an opioid receptor agonist or clonidine for opioid detoxification. In these trials, lofexidine dosing was titrated to a maximum of 1.6-3.2 mg/day in divided doses for a total of 5-18 days. The data suggest that lofexidine has positive efficacy in reducing opioid withdrawal symptoms and is at least as effective as the opioid receptor agonists utilized for detoxification. Not all withdrawal symptoms are alleviated by alpha(2)-agonists, with many patients complaining of insomnia and aching. The most common adverse event with lofexidine in the Phase 3 trial was insomnia. Hypotension was also reported; however, the studies comparing clonidine with lofexidine suggest decreased incidence and severity of adverse events with lofexidine[2].

Absorption, Distribution and Excretion
Lofexidine has a good oral bioavailability and the peak plasma concentration occurs after 2-5 hours of oral administration. The bioavailability is registered to be even higher than 72%. About 30% of the administered dose of lofexidine is lost during first-pass metabolism. The absorption is registered to be very rapidly recirculated in the gut. After oral administration of 0.8 mg of lofexidine, a maximal dose of 1.26 ng/ml is achieved after 3 hours.
The elimination of lofexidine is primarily through the renal system and it represents 94% of the administered dose while elimination in feces corresponds to only 0.93%. From the eliminated dose in urine, about 10% is formed by unchanged drug and 5% is constituted by the first hydrolysis product N-(2-aminoethyl)-2-(2,6-dichlorophenoxy)propanamide. 2,6-dichlorophenol represents the majority of the administered dose by occupying about 80% of the administered dose.
Lofexidine has a volume of distribution of 300 L, indicating that it distributes readily into the tissues.
The total elimination clearance following intravenous administration is 17.6 L/h.

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Metabolism / Metabolites
Lofexidine metabolic ratio is highly variable among people. It is metabolized mainly by the activity of CYP2D6 and in a minor degree by CYP1A2 and CYP2C19. These enzymes catalyze the hydroxylation of lofexidine and the opening of imidazoline ring to form N-(2-aminoethyl)-2-(2,6-dichlorophenoxy)propanamide. This metabolite is deamidated and forms 2-(2,6-dichlorophenoxy) propionic acid and 2,6-dichlorophenol. These three main metabolites are inactive.

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Biological Half-Life
The reported elimination half-life of lofexidine is 11 hours.

human TDLo oral 270 ug/kg/6W-I BEHAVIORAL: SOMNOLENCE (GENERAL DEPRESSED ACTIVITY); BEHAVIORAL: HEADACHE; GASTROINTESTINAL: CHANGES IN STRUCTURE OR FUNCTION OF SALIVARY GLANDS Arzneimittel-Forschung. Drug Research., 32(976), 1982 [PMID:6890373]
mouse LD50 oral 54 mg/kg Arzneimittel-Forschung. Drug Research., 32(966), 1982 [PMID:6890371]
mouse LD50 intravenous 8 mg/kg SENSE ORGANS AND SPECIAL SENSES: OTHER: EYE; BEHAVIORAL: CONVULSIONS OR EFFECT ON SEIZURE THRESHOLD; BEHAVIORAL: ATAXIA Arzneimittel-Forschung. Drug Research., 32(955), 1982 [PMID:6890369]
dog LD50 oral 70 mg/kg SENSE ORGANS AND SPECIAL SENSES: OTHER: EYE; BEHAVIORAL: CONVULSIONS OR EFFECT ON SEIZURE THRESHOLD; BEHAVIORAL: ATAXIA Arzneimittel-Forschung. Drug Research., 32(955), 1982 [PMID:6890369]
dog LD50 intravenous 8 mg/kg SENSE ORGANS AND SPECIAL SENSES: OTHER: EYE; BEHAVIORAL: CONVULSIONS OR EFFECT ON SEIZURE THRESHOLD; BEHAVIORAL: ATAXIA Arzneimittel-Forschung. Drug Research., 32(955), 1982 [PMID:6890369]

[1]. The preclinical discovery of lofexidine for the treatment of opiate addiction. Expert Opin Drug Discov. 2014 Nov;9(11):1371-7.

[2]. Lofexidine, an {alpha}2-receptor agonist for opioid detoxification. Ann Pharmacother. 2010 Feb;44(2):343-51.

LOFEXIDINE HYDROCHLORIDE is a small molecule drug with a maximum clinical trial phase of IV (across all indications) that was first approved in 2018 and is indicated for substance withdrawal syndrome and has 1 investigational indication.

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Areas covered: The following article highlights lacunae in extant knowledge about the molecular pharmacology of lofexidine. Furthermore, the article provides a brief discussion on the nature and shortcomings of clinical trials for this drug that have been conducted over the past 30 years across the world. It also provides a discussion of the market factors and regulatory considerations responsible for the rather limited use of lofexidine thus far. Expert opinion: Many lessons can be learned from the 40-year-long development of lofexidine. Indeed, unless there is an urgent need to address an unmet and/or immediate health threat, preclinical development is dictated by pharmacoeconomic considerations. Lofexidine would likely have been excluded for further development in this day and age given the existence and value of clonidine as well as the lack of insurance coverage for opiate addiction. It should be noted, however, that although there have been many oversights in the past, current experimentation and clinical trials are beginning to address the mistakes made through the exploration of single enantiomers and controlled-release preparations.[1]

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Objective: To review the pharmacology, toxicology, pharmacokinetics, efficacy, adverse effects, drug interactions, and dosage guidelines for lofexidine, an alpha(2)-agonist, for opioid detoxification. Data sources: Primary literature was identified through a MEDLINE search (1950-September 2009), EMBASE (1988-July 2009), International Pharmaceutical Abstracts (1970-September 2009), and the Cochrane Library (1996-September 2009) using the key words lofexidine and opioid withdrawal. Abstracts were included in the absence of published results of studies. Study selection and data extraction: Studies published in English-language literature reporting on animal and human pharmacology, toxicology, and pharmacokinetics were included in addition to clinical trials using lofexidine for opioid detoxification in comparison to placebo or active controls. Conclusions: Lofexidine appears to be a promising agent for opioid detoxification. If approved, it would be the first nonopioid agent approved for this indication. Further large-scale controlled studies are needed to identify the safest, most effective dosage regimen required to achieve opioid detoxification.[2]

C11H13CL3N2O

295.59

294.009

C, 44.70; H, 4.43; Cl, 35.98; N, 9.48; O, 5.41

21498-08-8

Lofexidine; 31036-80-3; Lofexidine-d4 hydrochloride; 1206845-57-9

30667

White to off-white solid powder

421.5ºC at 760 mmHg

230-232ºC

208.7ºC

6.35E-07mmHg at 25°C

3.328

2

2

3

17

263

0

CC(C1=NCCN1)OC2=C(Cl)C=CC=C2Cl.[H]Cl

DWWHMKBNNNZGHF-UHFFFAOYSA-N

InChI=1S/C11H12Cl2N2O.ClH/c1-7(11-14-5-6-15-11)16-10-8(12)3-2-4-9(10)13;/h2-4,7H,5-6H2,1H3,(H,14,15);1H

2-[1-(2,6-dichlorophenoxy)ethyl]-4,5-dihydro-1H-imidazole;hydrochloride

Lofexidine Hydrochloride; Lofetensin; 21498-08-8; LOFEXIDINE HCl; Lofetensin; Loxacor; Lofexidine.HCl; Lofexidine (hydrochloride); Britlofex;Brand name Lucemyra; Lofexidine HCl; Loxacor;Lofexidine mono-hydrochloride; lofexidine (+-)-isomer

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2.08 mg/mL (7.04 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.08 mg/mL (7.04 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.08 mg/mL (7.04 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: 100 mg/mL (338.31 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication.

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 (Please use freshly prepared in vivo formulations for optimal results.)