Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2012 Publisher: RB Pharmaceuticals Ltd 103 – 105 Bath Road, Slough Berkshire SL1 3UH
OPIOID ANALGESIC (N: central nervous system)
Buprenorphine is an opioid partial agonist/antagonist which attaches itself to the µ (mu) k (kappa) receptors of the brain. Its activity in opioid maintenance treatment is attributed to its slowly reversible link with the µ receptors which, over a prolonged period, minimises the need of the addicted patient for drugs.
During clinical pharmacologic studies in opiate-dependent subjects, buprenorphine demonstrated a ceiling effect on a number of parameters, including positive mood, “good effect”, and respiratory depression.
When taken orally, buprenorphine undergoes first-pass hepatic metabolism with N-dealkylation and glucuroconjungation in the small intestine. The use of this medication by oral route is therefore inappropriate.
Peak plasma concentrations are achieved 90 minutes after sublingual administration and the maximal dose- concentration relationship is linear, between 2 mg and 16 mg.
The absorption of buprenorphine is followed by a rapid distribution phase and a half – life of 2 to 5 hours.
Buprenorphine is oxidatively metabolised by 14-N-dealkylation to N-desalkyl-buprenorphine (also known as norbuprenorphine) via cytochrome P450 CYP3A4 and by glucuroconjungation of the parent molecule and the dealkylated metabolite. Norbuprenorphine is µ (mu) agonist with weak intrinsic activity.
Elimination of buprenorphine is bi- or tri- exponential, with long terminal elimination phase4 of 20-25 hours, due in part to reabsorption of buprenorphine after intestinal hydrolysis of the conjugated derivative, and in part to the highly lipophilic nature of the molecule.
Buprenorphine is essentially eliminated in the faeces by biliary excretion of the glucuroconjugated metabolites (80%), the rest being eliminated in the urine.
Acute toxicity of buprenorphine was determined in the mouse and rat following oral and parenteral administration. The median lethal dose (LD50) in the mouse were 26, 94 and 261 mg/kg for intravenous, intraperitoneal and oral administration, respectively. The LD50 values in a rat were 35, 243 and 600 mg/kg for intravenous, intraperitoneal and oral administration, respectively.
When beagles were dosed continuously subcutaneously for one month, rhesus monkeys orally for one month and rats and baboons intramuscularly for six months, buprenorphine showed remarkably low tissue and biochemical toxicities.
From teratology studies in rats and rabbits, it was concluded that buprenorphine is not embryotoxic or teratogenic, and it does not have any marked effects on weaning potential. There were no adverse effects of fertility of general reproductive function in rats, although at the highest intramuscular dose (5 mg/kg/day) the mothers experienced some difficulty in parturition and there was a high neonatal mortality.
Minimal to moderate hyperplasia of the bile duct with associated peribiliary fibrosis occurred in dogs following 52 weeks of oral dosing of 75 mg/kg/day.
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