Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study is not done according to OECD guideline, but it is a well documented study.

Data source

Reference
Reference Type:
publication
Title:
The reproducibility of quinine bioavailability.
Author:
Paintaud, G., Alván, G. and Ericsson, Ö.
Year:
1993
Bibliographic source:
Br J Clin Pharmacol. 35(3):305-307

Materials and methods

Objective of study:
toxicokinetics
Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Six subjects, three males and three females, participated in the study. Their mean age (range) was 31 (21-40) years and their mean body weight was 72 (52-85) kg. All were found to be healthy by routine clinical examination and laboratory tests. They had taken no drugs for at least 1 week before the study. One female subject and two male subjects were smoking between 15 to 20 cigarettes per day. The subjects were given an i.v. infusion dose of quinine. The infusion was started at 08.00 h, after a light breakfast had been taken at home. The oral intakes were a coffee (from 0.33 to 2 h after the dose) and lunch (from 3 to 5 h after the dose), after which there were no dietary restrictions. The subjects were resting during the first 3 h after dosing. For the i.v. infusion dose, blood samples (2 ml) were collected in heparinised tubes at the time of drug intake, every 20 min until 3 h, every 30 min from 3 to 12 h and at 24, 28 and 32 h. Plasma was separated within 1 h after collection by centrifugation for 7 min at 2000 g. The samples were stored at -20° C until assay. Quinine was measured by a reversed phase HPLC method with fluorescence detection. The excitation and emission wavelengths of the detector were set at 350 and 446 nm, respectively. Plasma samples (100 µl) were alkalinized with sodium hydroxide, extracted with toluene and reextracted with phosphate buffer. The column was an Ultrasphere ODS 3 µm, 75 x 4.6 mm. The eluent was prepared by mixing 480 ml phosphate buffer 0.1 mol/L, pH 1.9, 30 ml acetonitrile, 10 ml tetrahydrofuran and 8 ml triethylamine and adjusting pH to 3.5 with NaOH 5 mol-1. The flow rate was 1.0 ml/min. The within-assay coefficient of variation was 2-4%, and the day-to-day coefficient of variation was less than 4% during the study. The limit of determination was 2 nmol/L plasma. Peak plasma concentrations (Cmax) and the time to reach peak concentrations (tmax) of quinine were noted. The terminal elimination rate constant (λz) was estimated by linear regression of the log linear portion of the terminal elimination phase. Areas under the plasma drug concentration-time curve (AUC) were calculated by the linear trapezoidal method with extrapolation to infinity. The mean percentage of the AUC extrapolated beyond the last data point was 13% for the oral doses and 16% for the infusion. Plasma clearance (CL), fraction of the dose absorbed (F), mean residence time (MRT) and volume of distribution at steady state (Vss) were calculated after intravenous administration by standard equations (Gibaldi &Perrier, 1982).
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid: particulate/powder
Remarks:
migrated information: powder
Details on test material:
- Name of test material (as cited in study report): Quinine dihydrochloride
- other: obtained from Apoteksbolaget, Sweden
Radiolabelling:
no

Test animals

Species:
human
Sex:
male/female

Administration / exposure

Route of administration:
intravenous
Vehicle:
other: solution of quinine dihydrochloride in isotonic NaCl
Duration and frequency of treatment / exposure:
The subjects were given an intravenous infusion dose of quinine.
Doses / concentrations
Remarks:
Doses / Concentrations:
The subjects were given an i.v. infusion dose of quinine dihydrochloride. The i.v. dose was 15 mg/kg and was administered as a constant rate infusion over 6 h. The infusion was prepared by dissolution of quinine dihydrochloride powder in isotonic NaCl to obtain a final concentration of 2.5 mg/ml. The quinine salt has a molecular weight of 397 and the intended dose was equivalent to 12.24 mg/kg of quinine base. Five subjects received an i.v. dose of 11.97 mg/kg and one subject received 6.03 mg/kg of quinine base over 3 h.
No. of animals per sex per dose:
Six subjects, three males and three females
Their mean age (range) was 31 (21-40) years and their mean body weight was 72 (52-85) kg. All were found to be healthy by routine clinical examination and laboratory tests. They had taken no drugs for at least 1 week before the study. One female subject and two male subjects were smoking between 15 to 20 cigarettes per day.
Control animals:
no
Details on study design:
The infusion was started at 08.00 h, after a light breakfast had been taken at home. The oral intakes were a coffee (from 0.33 to 2 h after the dose) and lunch (from 3 to 5 h after the dose), after which there were no dietary restrictions. The subjects were resting during the first 3 h after dosing. For the i.v. infusion dose, the blood samples (2 ml) were collected in heparinised tubes at the time of drug intake, every 20 min until 3 h, every 30 min from 3 to 12 h and at 24 h, 28 h and 32 h. Plasma was separated within 1 h after collection by centrifugation for 7 min at 2000 g. The samples were stored at -20° C until assay.
Details on dosing and sampling:
PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled (delete / add / specify): blood and plasma
- Time and frequency of sampling: oral doses: every 20 min until 3 h, every 30 min from 3 to 12 h and at 24, 28 and 32 h. Plasma was separated within 1 h after collection

Results and discussion

Toxicokinetic / pharmacokinetic studies

Toxicokinetic parametersopen allclose all
Test no.:
#1
Toxicokinetic parameters:
AUC: 321 µmol/L* h
Test no.:
#1
Toxicokinetic parameters:
half-life 1st: 11.3 h
Test no.:
#1
Toxicokinetic parameters:
other: MRT i.v. 14.9 h

Metabolite characterisation studies

Metabolites identified:
not measured

Any other information on results incl. tables

Pharmacokinetic parameters of quinine dihydrochloride calculated from plasma concentrations

    AUC (µmol*h/L)  t1/2,z(h)  MRT i.v. (h) Vss(1/kg)   CL (ml*min-1*kg-1)  CVw (%)
 Quinine dihydrochloride  321 (71)  11.3 (3.1)  14.9 (4.3)  1.72 (0.38)  2.00 (0.5)  10

(normalised to a 6 h infusion for subject 4),

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): bioaccumulation potential cannot be judged based on study results
The AUC of quinine dihydrochloride was 321 µmol/L *h. The half-life of quinine dihydrochloride in plasma was 11.3 hours.
Executive summary:

In the study published by Paintaud, 1993 the pharmacokinetic of quinine dihydrochloride was determined after intravenous infusion. The AUC of quinine diydrochloride was 321 µmol/L *h and the half-life in plasma was 11.3 hours.