One, Orlis, what is he?
Orlistat is a lipase inhibitor, which acts by inhibiting the absorption of dietary fat.
The chemical structure of orlistat is (S)-2- formylamino -4- methyl-valeric acid (S)- 1-[(2S, 3S)-3- hexyl -4- oxo -2- oxyalkyl] methyl]-dodecyl ester. Its empirical formula is C29H53NO5 and its molecular weight is 495.7. It is a diastereomer molecule with four chiral centers and has negative optical rotation at 529nm in ethanol.
Orlistat is a white to white crystalline powder. Orlistat is almost insoluble in water, soluble in chloroform and extremely soluble in methanol and ethanol. Orlistat has no pKa in the physiological pH range.
Second, the clinical pharmacology of orlistat
1, mechanism of action
Orlistat is a reversible lipase inhibitor. By forming valence bonds with serine residues with lipase activity in stomach and pancreas, it plays a therapeutic role in stomach and small intestine cavity. Therefore, inactivated enzymes cannot hydrolyze dietary fat in the form of triglycerides into absorbable free fatty acids and monoglycerides. Because undigested triglycerides are not absorbed, the resulting calorie deficiency may have a positive effect on weight control. Therefore, this activity does not require systemic absorption of drugs. At the recommended therapeutic dose of 120 mg, orlistat inhibited the absorption of dietary fat by about 30% three times a day.
2. Pharmacokinetics
absorb
Total body contact with orlistat is the smallest. After oral administration of 360 mg 14C orlistat, the plasma radioactivity reached its peak in about 8 hours. The plasma concentration of intact orlistat is close to the detection limit (
In the study of oral administration of 150 and 1000 mg/kg to male rats and 100 and 1000 mg/kg/ day to male dogs, the average absolute bioavailability of intact orlistat was evaluated, and it was found that rats and dogs were 0.1day respectively.
distribute
In vitro binding rate of orlistat to plasma protein >: 99% (lipoprotein and albumin are the main binding proteins). Orlistat is minimally divided into red blood cells.
metabolism
According to animal experimental data, the metabolism of orlistat may mainly occur in the gastrointestinal wall. According to the study on the mass balance of oral 14C orlistat in obese patients, two metabolites, M 1(4 yuan lactone ring hydrolysis) and M3(M 1 partial cleavage with N- formylleucine), account for about 42% of the total plasma radioactivity. M 1 and M3 have an open b- lactone ring and very weak lipase inhibitory activity (lower than Bioli stat 1000 times and 2500 times respectively). In view of this low inhibitory activity and low plasma level at therapeutic dose (M 1 and M3 are 26 ng/mL and 108 ng/mL on average 2 to 4 hours after administration, respectively), these metabolites are considered to have nothing to do with pharmacology. The half-life of the primary metabolite M 1 is short (about 3 hours), while the disappearance speed of the secondary metabolite M3 is slow (the half-life is about 13.5 hours). In obese patients, the level of M 1 (instead of M3) in steady-state plasma increases in proportion to the dose of orlistat.
eliminate
After a single oral administration of 360mg 14C orlistat to normal weight and obese subjects, it was found that fecal excretion of unabsorbed drugs was the main elimination route. Orlistat and its metabolites M 1 and M3 are also affected by bile excretion. About 97% of radioactive substances are discharged through feces; 83% of radioactive materials were found to be unchanged orlistat. The cumulative renal excretion of total radioactivity is less than 2% of the dose of 360 mg 14C orlistat. The time to complete excretion (feces plus urine) is 3-5 days. The distribution of orlistat in normal weight and obese people is similar. According to limited data, the half-life of orlistat is between 1-2 hours.
Special population
Due to the small amount of drug absorption, no research has been carried out on special groups (elderly people, patients of different races, people with liver and renal insufficiency).
paediatrics
The plasma concentrations of orlistat and its metabolites M 1 and M3 are similar to those of adults at the same dose level. The daily fecal fat excretion of orlistat group and placebo group accounted for 27% and 7% of the dietary intake, respectively.
drug interaction
wine
In a multi-dose study of 30 normal weight subjects, the combination of orlistat and 40 grams of alcohol (for example, about 3 glasses of wine) did not lead to changes in alcohol pharmacokinetics, orlistat pharmacodynamics (fecal fat excretion) or orlistat systemic exposure.
Cyclosporin
Preliminary data on the interaction between orlistat and cyclosporine showed that the blood concentration of cyclosporine decreased when orlistat was combined with cyclosporine (see warning).
digoxin
In 12 normal weight subjects, oral administration of 120 mg orlistat three times a day for six days did not change the pharmacokinetics of a single dose of digoxin.
Fat-soluble vitamin supplements and analogues
A pharmacokinetic interaction study showed that when β -carotene supplement was combined with Sinisan, its absorption was reduced by 30%. Orlistat inhibits the absorption of vitamin E acetate supplement by about 60%. The effect of orlistat on the absorption of vitamin D, vitamin A and nutritional vitamin K is not clear.
glibenclamide
In 12 normal weight subjects, orlistat was taken 80 mg three times a day for 5 days continuously, and orlistat did not change the pharmacokinetics or pharmacodynamics of glibenclamide (lowering blood sugar).
Levothyroxine
It is reported that patients who received the combination therapy of orlistat and levothyroxine after marketing developed hypothyroidism (see Adverse Reactions: Other Clinical Studies or Post-marketing Monitoring). Patients taking orlistat and levothyroxine at the same time should monitor the changes of thyroid function. The interval between levothyroxine and orlistat should be at least 4 hours.
Nifedipine (sustained-release tablets)
In 17 normal weight subjects, orlistat 120mg was taken three times a day for 6 days, but orlistat did not change the bioavailability of nifedipine (sustained release tablets).
oral contraceptive
In 20 normal-weight female subjects, oral contraceptive 120 mg, three times a day for 23 days, had no change in ovulation inhibition effect.
phenytoin sodium
In 12 normal weight subjects, orlistat 120 mg was given three times a day for 7 days, and the pharmacokinetics of a single dose of 300 mg phenytoin sodium was not changed by orlistat.
Pravastatin
In a two-way crossover study of 24 patients with normal weight and mild hypercholesterolemia, orlistat was taken 120 mg three times a day for 6 days, and orlistat did not affect the pharmacokinetics of pravastatin.
Rodenticide
In 12 normal weight subjects, taking 120 mg orlistat three times a day for 16 days did not change the pharmacokinetics (R- and S- enantiomers) or pharmacodynamics (prothrombin time and serum factor VII) of warfarin. Although the low carboxyl osteocalcin (a sign of vitamin K nutritional status) has not changed after taking orlistat, the vitamin K level of subjects taking orlistat tends to decrease. Therefore, because orlistat may reduce the absorption of vitamin K, patients taking warfarin with long-term stable dose should closely monitor the changes of coagulation parameters after taking orlistat.
Carcinogenesis, mutation, fertility disorder
Carcinogenicity studies in rats and mice showed that orlistat had no carcinogenicity at doses as high as 1000 mg/kg and 1500mg/kg/ day, respectively. For mice and rats, these doses are 38 times and 46 times of the daily dose of human body calculated according to the area under the concentration-time curve of the total drug-related substances, respectively.
In Ames test, mammalian forward mutation test (V79/HPRT), in vitro human peripheral blood lymphocyte production test, in vitro cultured rat hepatocytes DNA synthesis test (UDS) and in vivo mouse micronucleus test, orlistat did not detect mutagenic or genotoxic activity.
In the study of fertility and reproduction, the dose of 400mg/kg/ day was given to rats, and orlistat had no obvious adverse reactions. This dose is 12 times of the daily dose of human body calculated according to the surface area of human body (mg/m2).
Pregnant
Teratogenesis: pregnancy type B.
The teratogenic effects of rats and rabbits were studied at a dose as high as 800 mg/kg/day. Neither study showed embryo toxicity or teratogenicity. This dose is 23 times and 47 times of the daily dose of human body calculated according to the body surface area (mg/m2) of rats and rabbits respectively.
In the middle and high dose groups of teratogenic study in rats, the incidence of ventricular dilatation increased. These doses are 6 times and 23 times of the daily dose calculated on the basis of human body surface area (mg/m2) at the middle and high dose levels, respectively. This finding was not repeated in two other teratogenic studies in rats with similar doses.
At present, there is no sufficient and good controlled study on pregnant women taking orlistat. Because animal reproductive research cannot always predict human reactions, it is not recommended to use orlistat during pregnancy.
Lactating mother
It is not clear whether orlistat is secreted in breast milk. Therefore, lactating women should not take coriander.
Dose response relationship
A simple maximum effect (Emax) model is used to define the dose-response curve between the daily dose of orlistat and fecal fat excretion, which is the representative of gastrointestinal lipase inhibition. The dose-response curve shows that the daily dose of up to 400 mg has a steep part, followed by a plateau period of high dose. When the dose is greater than 120 mg, three times a day, the percentage of effect increase is very small.
clinical research
Observational epidemiological studies have confirmed the relationship between obesity and visceral fat and cardiovascular diseases, type 2 diabetes, some cancers, gallstones, some respiratory diseases and the increase of total mortality. These studies show that maintaining weight loss may bring health benefits to obese patients who have or may have weight-related diseases. this
The long-term effects of orlistat on obesity-related morbidity and mortality have not been determined.
In the four-year XENDOS study and seven long-term (1-2 years) multicenter, double-blind, placebo-controlled clinical trials, the effects of orlistat on weight loss, weight maintenance and weight recovery, as well as some diseases (such as type 2 diabetes, blood lipid and blood pressure) were evaluated. In the first year of treatment, a two-year study assessed weight loss and maintenance. In the second year of treatment, some studies evaluated sustained weight loss and weight maintenance, while others evaluated the effect of orlistat on weight recovery. These studies included 2800 patients treated with orlistat and 1400 patients treated with placebo. Most patients have obesity-related risk factors and complications. In the XENDOS study involving 3304 patients, besides weight management, the onset time of type 2 diabetes was also evaluated. In all these studies, orlistat and placebo therapy refer to orlistat plus diet and placebo plus diet therapy respectively.
During weight loss and weight maintenance, a balanced low-calorie diet is recommended to all patients, with the aim of reducing calorie intake by about 20% and providing 30% calories from fat. In addition, all patients received nutrition counseling.
One-year results: weight loss, weight maintenance and risk factors
Weight loss was observed within 2 weeks after the start of treatment and lasted for 6 to 12 months.
The summary data of five clinical trials showed that the total average weight loss of patients treated with orlistat was 65,438 02.4 pounds and 65,438 03.4 pounds respectively, and that of patients treated with placebo was 6.2 pounds and 5.8 pounds respectively. During the four-week introduction of placebo, the same patients also observed an additional 5-6 pounds of weight loss. Among the patients who completed 1 year treatment, 57% patients who received orlistat (taken three times a day 120 mg) and 3 1% patients who received placebo lost at least 5% of their baseline weight.
Third, the National Bank Edition.
The domestic versions of orlistat mainly include Aili, Yasu and Besunyen, with stable effect, but the disadvantage is that the price is higher than many countries.
Alternative versions include: Indian version, Thai version, Japanese version, Korean version, etc. Among them, the Indian version and the Thai version are cheap, thanks to their patents and labor costs. Please consult the landlord for more channels.