Alitame is stable in dry, room temperature conditions but undergoes degradation at elevated temperatures or when in solution at low pH. Alitame can degrade in a one-stage process to aspartic acid and alanine amide (under harsh conditions) or in a slow two-stage process by first degrading to its beta-aspartic isomer and then to aspartic acid and alanine amide.
Four male subjects were administered an oral dose of 14C-alitame (50 mCi; 1 mg/kg bw). Blood samples were taken at various times up to 48 hr. Exhaled 14CO2 was measured at various times up to 8 hr. Urine and faeces were collected over 5 days. Plasma radioactivity levels peaked between 8 and 18 hr and decreased rapidly within the first 48 hr, indicating slow but extensive absorption followed by rapid excretion. There was no significant increase in exhaled 14CO2 above zero. Urinary radioactivity was maximal between 12 and 24 hr with approximately 50% of radioactivity excreted in the first 24 hr and 90% within 5 days Fecal elimination accounted for 7-10% of the total dose in 3 subjects and 2% in the 4th subject. The major urinary metabolites were alanine tetramethylthietane amide sulfoxide and alanine tetramethyl- thietane amide glucuronide. Minor metabolites were alanine tetramethylthietane amide and alanine tetramethylthietane amide sulfone. The glucuronide was the major urinary metabolite in the first 24 hr whereas the sulfoxide was the major metabolite in the 24-48 hr period. Unchanged alitame constituted less than 1% of the total urinary radioactivity. In feces, all of the radioactivity consisted of unchanged alitame and alanine tetramethylthietane amide. In plasma, the major part of the radioactivity (80%) consisted of alanine tetramethylthietane amide and its glucuronide. In contrast to rats and dogs, the major urinary metabolite in humans was found to be the glucuronide of alanine tetramethylthietane amide.
Following a single oral dose of 50 mg/kg bw 14C-alitame or a diet containing 3000 mg/kg 14C-alitame, metabolites identified /in mice/ were D-alanine tetramethylthietane amide sulfoxide (64.3%), D-alanine tetramethylthietane amide (24.7%), and unchanged alitame (0.9%). The remainder metabolites (10.1%) were not identified. Fecal radioactivity was identified as 39.5% unchanged alitame, 51.5% D-alanine tetramethyltbietane amide and 4.6% was not identified.
In a study to examine metabolites in plasma, a group of Long-Evans rats received a single oral dose of 50 mg/kg bw 14C-alitame. Two rats were bled serially to determine the time course of radioactivity and a further 3 male and 3 female rats were killed at 6 hr and the plasma radioactivity was assayed by HPLC. Maximum plasma levels occurred at 4 to 6 hr after administration. The major metabolite was alanine tetramethylthietane amide sulfoxide (70% of the total radioactivity), in both the free and acetylated forms with unchanged alitame only 1% of the total radioactivity.
In a study to examine metabolites in urine, 4 male and 4 female Long-Evans rats were administered a single oral dose of 5 mg/kg bw 14C-alitame. Urine and feces were collected over a 24-hour period and analyzed by HPLC. The major urinary metabolite was alanine tetramethylthietane amide sulfoxide (75-80%), in both free and acetylated forms, with unchanged alitame only 1% of the total radioactivity.
In a study to examine metabolites in feces, two Long-Evans rats received a single oral dose of 50 mg/kg bw or 1000 mg/kg bw 14C-alitame. Urine and feces were collected over 24 hr and analyzed by HPLC. The major product in the feces was unchanged alitame (70% of the radioactivity). A second metabolite was identified as alanine tetramethylthietane amide (23%).
/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/
/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/
/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/
/HUMAN EXPOSURE STUDIES/ In a 90-day double-blind tolerance study in diabetic subjects, groups of male and female subjects having either type I or type II diabetes (75 treated, 80 control) were administered either alitame in capsules divided over three meals at dose level of 10 mg/kg bw/day for 90 days, or placebo in the same manner. This dose was chosen because it is ten times greater than the estimated daily intake if all sucrose in the diet were replaced with alitame. Subjects were included on the following criteria: diabetics of type I and type II, either sex and aged between 15 and 70 years with stable diabetic therapy; fasting blood glucose <250 mg/dL; free from investigational drugs; had not suffered a myocardial infarction within the previous 6 months; and had either no hypertension or it was controlled. ... At the end of the study period, 16 treated and 9 control subjects had discontinued from the programe and, of these, 5 treated and 2 control subjects withdrew due to illness. No subjects discontinued due to side effects or abnormal laboratory parameters related to alitame treatment. Side-effects were observed in 29% of treated subjects and 25% of control subjects. Gastrointestinal disturbances were the most common side-effect. Incidence and severity of particular side-effects were relatively evenly distributed between the groups. No significant changes were noted in either the control or treated groups with respect to diabetic control, clinical chemistry, hematological or urinary parameters. No treatment-related effects were apparent from the physical examinations, blood pressure and pulse rate, temperature, body weight or EKG recordings. Alitame at a dose of 10 mg/kg/bw/day for 90 days was well tolerated by the type I and type II diabetic patients who continued in this study. There was no effect of alitame at this dose level on the ability to control serum glucose levels by these diabetic patients.
/HUMAN EXPOSURE STUDIES/ In a 90-day double-blind tolerance study, groups of male and female subjects (77 treated, 80 controls) were administered either alitame in capsules divided over three meals at a dose level of 10 mg/kg bw/day for 90 days, or placebo in the same manner. This dose was chosen because it is 10 times greater than the estimated daily intake if all sucrose in the diet were replaced with alitame. Subjects were assessed throughout the study period for side-effects (by interview and observation). Other tests included blood pressure, temperature, body weight, electrocardiogram, and ophthalmoscopic examination. Various clinical pathology parameters were also measured. Microsomal activation was estimated from the elimination kinetics of aminopyrine at pre-dosing and at weeks 6 and 13 of treatment. Plasma and urine samples were collected at various time points throughout the study. Four treated subjects and 2 control subjects discontinued from the study due to side effects (angioedema of the lips, maculopapular rash, urticaria (wheals) with erythema in treated subjects, and tinnitus, dry eyes and abdominal cramps in the control subjects). A rechallenge with alitame after 6 months produced none of the above symptoms, making the possibility of allergic reaction very unlikely. There were no treatment-related changes in blood pressure, pulse, temperature or body weight. Electrocardiograms and ophthalmological examinations were unremarkable. Hematological parameters were similar in treated and control subjects. Measurement of aminopyrine elimination rates at 6 and 13 weeks did not reveal any increase in hepatic microsomal enzyme activity due to alitame treatment.
A group of 5 male CD-1 mice was administered by gavage a single dose of 50 mg/kg bw 14C-alitame in distilled water. A second group of 5 male CD-1 mice was fed a diet containing 14C-alitame at a concentration of 0.3%, equal to 350 mg/kg bw. Following the gavage dose, 77% of the radioactivity was recovered in urine in a 24-hour period. About 50% of the administered dose was excreted between 4 and 20 hr. Fecal radioactivity was not measured. Following dietary administration, 60% of the radioactivity was found in urine and 32% in feces.
A male Long-Evans rat with a bile duct cannula was administered a single oral dose of 50 mg/kg bw 14C-alitame. Bile and urine were collected for 48 hr. In a second study, 4 male and 4 female Long-Evans rats were administered a single oral dose of 5 mg/kg bw 14C-alitame. Urine and feces were collected for 7 days and analyzed for radioactivity. In the single animal study, 83% of the radioactivity was recovered, with 14% in bile and 69% in urine over 48 hr, indicating extensive absorption. In the group study, most of the radioactivity was recovered in urine (83% in males, and 95% in females) in a 24-hour period. Fecal radioactivity was 20% in males and 4% in females during 24 hr with little detected after that time.
In a study to investigate tissue distribution in rats, a group of 24 male and 24 female Long-Evans rats received by gavage a single dose of 5 mg/kg bw 14C-alitame. Animals in groups of 3 males and 3 females were killed at 2, 6 or 24 hr, and at 2, 3, 7, 14 or 29 days and tissue levels determined. In most tissues, the half-life of clearance was 3 to 6 hr and the levels were below the level of detection by 7 days. Residue levels of radioactivity in the eyes decreased much more slowly than in other tissues and levels of 0.08 mg/kg were detected at day 29.
In a study to examine the potential for transplacental transfer of alitame, pregnant Long-Evans rats received a single oral dose of 1000 mg/kg bw 14C-alitame on day 13 of gestation. Four animals were sacrificed 6 or 24 hr after treatment and maternal plasma and fetuses were examined for radioactivity. Radioactivity was high in the plasma of dams at 6 and 24 hr, and high levels were also found in the fetuses at these times, indicating transplacental transfer of alitame.
