Tiapride

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

secondary literature

Data source

Reference

Reference Type:

review article or handbook

Title:

Tiapride. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in geriatric agitation.

Author:

Steele JW

Year:

1993

Bibliographic source:

Drugs Aging. 1993; 3(5): 460-78.

Materials and methods

Objective of study:

absorption

distribution

excretion

GLP compliance:

not specified

Test material

Test material information

Details on test material:

The SMILES included in the reference substance linked in Section 1 (General information) was used as model input.

Specific details on test material used for the study:

not specified

Results and discussion

Any other information on results incl. tables

The methods used for measuring concentrations of tiapride and its metabolites in body fluids include gas chromatography, high performance liquid chromatography and radioactivity from [3H]tiapride as measured by liquid scintillation. The pharmacokinetic properties of tiapride after a single oral dose have been investigated in healthy volunteers and in patients with Huntington's disease or renal insufficiency, and after multiple oral doses in patients with chronic schizophrenia associated with tardive dyskinesia. Pharmacokinetic properties have also been investigated after single intravenous and intramuscular doses in healthy volunteers, and after single oral and intramuscular doses in elderly patients and volunteers. A single oral dose of a slow release formulation has also been investigated in healthy volunteers. Since the therapeutic dosages of tiapride varied widely from dosages used in the above studies, and since plasma drug concentrations during therapy have not been measured, these pharmacokinetic parameters have apparently had little impact on clinical use of the drug.

ABSORPTION

Experimental pharmacokinetic data related to tiapride are compatible with a linear 2-compartment model, with distribution into a peripheral compartment and elimination from a central compartment. The bioavailability in healthy volunteers was reported as a mean of 75.2% (47.3 to 98.9%) for oral and intramuscular dosage forms, or 66 to 78% unchanged drug for oral tiapride and 72 to 93% unchanged drug for intramuscular tiapride. In healthy volunteers, the presence of food increased the absorption of a single oral dose of tiapride 200mg by a mean of 29%. Following oral administration of single doses of tiapride 200mg to healthy European volunteers, mean maximum plasma concentrations (Cmax) were 1.73 and 1.55 mg/L for solution and tablets, respectively, and the corresponding mean times required to achieve Cmax (tmax) were 0.68 and 1.07h, respectively. In the same study, after a single intramuscular dose of tiapride 200mg, mean Cmax was 2.0 mg/L and tmax was 0.47h. The results of this and other studies are summarised in table III. Similar results were reported in elderly Asiatic patients, but with a slightly slower rate of absorption and a longer elimination half-life (4.72 and 5.75h after intramuscular and oral tiapride respectively). In a small group of patients with schizophrenia and tardive dyskinesia, or Huntington's disease, pharmacokinetic parameters were similar to those in younger volunteers, steady-state plasma tiapride concentrations were reached within 24 to 48h, and were similar to concentrations reached after a single dose in healthy volunteers. There was no evidence of drug accumulation but the percentage of renal clearance was lower in these patients. The investigators recommended that tiapride should therefore be given 3- to 4-times daily at regular intervals to maintain satisfactory plasma concentrations.

DISTRIBUTION

Distribution of tiapride in healthy volunteers and patients is rapid (absorption half-life; t 1/2α= 0.2h), and its volume of distribution (1.43 L/kg) suggests some accumulation in tissues. Protein binding was not detected. An in vitro study of human maternofetal transfer using isolated lobular perfusion technique showed that about 50% transfer of drug could be expected compared with antipyrine, and that protein binding was <4%. Using [14C]tiapride in rats and dogs, Strolin-Benedetti and colleagues (1978) detected significant radioactivity in the pituitary, representing concentrations of tiapride several-fold higher than those in plasma at all time intervals measured following single oral or intramuscular doses.

ELIMINATION

There was very little difference in tiapride elimination parameters between volunteers and patients, with the exception of a decreased percentage of :he dose eliminated in urine in the patient groups and a prolonged elimination half-life (t1/2β) in the study of Norman et al. (1987). These latter investigators ascribed this to the mean age of the patient group being about double that of the volunteers in other studies, and possibly as a result of the disease process. In patients with severe renal insufficiency, t1/2β was increased to 21.6 hours, indicating that careful adjustment of dosage is required in these patients. Marked differences in pharmacokinetic parameters between volunteers and patients with renal insufficiency have also been reported for sulpiride, a closely related benzamide drug. Data are lacking concerning the effects of age, disease, and concurrent medications on the pharmacokinetic parameters of tiapride. In man, renal excretion accounts for virtually total elimination of tiapride, mainly in the form of unchanged drug. N-(2-ethylaminoethyl)-2-methoxy-5-methylsulphonylbenzamide (N-de-ethyltiapride) and N-(2- diethylaminoethyl)-2-methoxy-5-methylsulphonylbenzamide N-oxide (tiapride N-oxide) have been identified as minor metabolites, and presumably are pharmacologically inactive. No conjugated forms have been found. Since elimination in man is essentially renal and the percentage of an oral dose metabolised is very low, it would not appear to be necessary to adjust dosage of tiapride in patients with hepatic insufficiency, although pharmacokinetic studies investigating this parameter have yet to be reported.

Applicant's summary and conclusion

Executive summary:

The methods used for measuring concentrations of tiapride and its metabolites in body fluids include gas chromatography, high performance liquid chromatography and radioactivity from [3H]tiapride as measured by liquid scintillation. The pharmacokinetic properties of tiapride after a single oral dose have been investigated in healthy volunteers and in patients with Huntington's disease or renal insufficiency, and after multiple oral doses in patients with chronic schizophrenia associated with tardive dyskinesia. Pharmacokinetic properties have also been investigated after single intravenous and intramuscular doses in healthy volunteers, and after single oral and intramuscular doses in elderly patients and volunteers. A single oral dose of a slow release formulation has also been investigated in healthy volunteers. Since the therapeutic dosages of tiapride varied widely from dosages used in the above studies, and since plasma drug concentrations during therapy have not been measured, these pharmacokinetic parameters have apparently had little impact on clinical use of the drug.

ABSORPTION

Experimental pharmacokinetic data related to tiapride are compatible with a linear 2-compartment model, with distribution into a peripheral compartment and elimination from a central compartment. The bioavailability in healthy volunteers was reported as a mean of 75.2% (47.3 to 98.9%) for oral and intramuscular dosage forms, or 66 to 78% unchanged drug for oral tiapride and 72 to 93% unchanged drug for intramuscular tiapride. In healthy volunteers, the presence of food increased the absorption of a single oral dose of tiapride 200mg by a mean of 29%. Following oral administration of single doses of tiapride 200mg to healthy European volunteers, mean maximum plasma concentrations (Cmax) were 1.73 and 1.55 mg/L for solution and tablets, respectively, and the corresponding mean times required to achieve Cmax (tmax) were 0.68 and 1.07h, respectively. In the same study, after a single intramuscular dose of tiapride 200mg, mean Cmax was 2.0 mg/L and tmax was 0.47h. The results of this and other studies are summarised in table III. Similar results were reported in elderly Asiatic patients, but with a slightly slower rate of absorption and a longer elimination half-life (4.72 and 5.75h after intramuscular and oral tiapride respectively). In a small group of patients with schizophrenia and tardive dyskinesia, or Huntington's disease, pharmacokinetic parameters were similar to those in younger volunteers, steady-state plasma tiapride concentrations were reached within 24 to 48h, and were similar to concentrations reached after a single dose in healthy volunteers. There was no evidence of drug accumulation but the percentage of renal clearance was lower in these patients. The investigators recommended that tiapride should therefore be given 3- to 4-times daily at regular intervals to maintain satisfactory plasma concentrations.

DISTRIBUTION

Distribution of tiapride in healthy volunteers and patients is rapid (absorption half-life; t 1/2α= 0.2h), and its volume of distribution (1.43 L/kg) suggests some accumulation in tissues. Protein binding was not detected. An in vitro study of human maternofetal transfer using isolated lobular perfusion technique showed that about 50% transfer of drug could be expected compared with antipyrine, and that protein binding was <4%. Using [14C]tiapride in rats and dogs, Strolin-Benedetti and colleagues (1978) detected significant radioactivity in the pituitary, representing concentrations of tiapride several-fold higher than those in plasma at all time intervals measured following single oral or intramuscular doses.

ELIMINATION

There was very little difference in tiapride elimination parameters between volunteers and patients, with the exception of a decreased percentage of :he dose eliminated in urine in the patient groups and a prolonged elimination half-life (t1/2β) in the study of Norman et al. (1987). These latter investigators ascribed this to the mean age of the patient group being about double that of the volunteers in other studies, and possibly as a result of the disease process. In patients with severe renal insufficiency, t1/2β was increased to 21.6 hours, indicating that careful adjustment of dosage is required in these patients. Marked differences in pharmacokinetic parameters between volunteers and patients with renal insufficiency have also been reported for sulpiride, a closely related benzamide drug. Data are lacking concerning the effects of age, disease, and concurrent medications on the pharmacokinetic parameters of tiapride. In man, renal excretion accounts for virtually total elimination of tiapride, mainly in the form of unchanged drug. N-(2-ethylaminoethyl)-2-methoxy-5-methylsulphonylbenzamide (N-de-ethyltiapride) and N-(2- diethylaminoethyl)-2-methoxy-5-methylsulphonylbenzamide N-oxide (tiapride N-oxide) have been identified as minor metabolites, and presumably are pharmacologically inactive. No conjugated forms have been found. Since elimination in man is essentially renal and the percentage of an oral dose metabolised is very low, it would not appear to be necessary to adjust dosage of tiapride in patients with hepatic insufficiency, although pharmacokinetic studies investigating this parameter have yet to be reported.