Quinine

Basic toxicokinetics

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 two identical oral doses of quinine on two separate occasions. The subjects took the oral doses of quinine after a light breakfast had been taken at home. The other 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. Following the oral doses, blood samples (2 ml) were collected in heparinised tubes at the time of drug intake, every 20 min until 3 h, every hour 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.

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

6119-47-7

Cas Number:

6119-47-7

IUPAC Name:

6119-47-7

Test material form:

other: tablet

Details on test material:

- Name of test material (as cited in study report): Quinine hydrochloride dihydrate- other: tablet obtained from KabiVitrum, Stockholm, Sweden

Radiolabelling:

no

Test animals

Species:

human

Sex:

male/female

Administration / exposure

Route of administration:

oral: unspecified

Vehicle:

unchanged (no vehicle)

Duration and frequency of treatment / exposure:

The subjects were given two identical oral doses of quinine on two separate occasions. The median (range) interval between the two oral doses was 11.5 (6-60) days.

Doses / concentrations

Remarks:

Doses / Concentrations:The subjects were given two identical oral doses of quinine on two separate occasions. The oral dose was as close as possible to 15 mg/kg and it was administered using 100 mg and 250 mg tablets of quinine hydrochloride dihydrate. The quinine salt has a molecular weight of 397 and the intended dose was equivalent to 12.24 mg/kg of quinine base. The actual mean oral dose was 12.06 mg/kg of quinine base.

No. of animals per sex per dose / concentration:

Six subjects, three males and three femalesTheir 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:

not specified

Details on study design:

The subjects took the oral doses of quinine after a light breakfast had been taken at home. The other 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. Following the oral doses, blood samples (2 ml) were collected in heparinised tubes at the time of drug intake, every 20 min until 3 h, every hour 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.

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 hour 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 parameters

Toxicokinetic parameters 1

Test no.:

#1

Toxicokinetic parameters:

AUC: 248 µmol/L* h

Toxicokinetic parameters 2

Test no.:

#1

Toxicokinetic parameters:

Cmax: 15.2 µmol/L

Toxicokinetic parameters 3

Test no.:

#1

Toxicokinetic parameters:

Tmax: 1.84 h

Toxicokinetic parameters 4

Test no.:

#1

Toxicokinetic parameters:

half-life 1st: 10.7 h

Toxicokinetic parameters 5

Test no.:

#2

Toxicokinetic parameters:

AUC: 245 µmol/L* h

Toxicokinetic parameters 6

Test no.:

#2

Toxicokinetic parameters:

Cmax: 15.7 µmol/L

Toxicokinetic parameters 7

Test no.:

#2

Toxicokinetic parameters:

Tmax: 2.01 h

Toxicokinetic parameters 8

Test no.:

#2

Toxicokinetic parameters:

half-life 1st: 10.9 h

Metabolite characterisation studies

Metabolites identified:

not specified

Any other information on results incl. tables

Pharmacokinetic parameters of quinine calculated from plasma concentrations after oral dosing

	First oral dose	Second oral dose	CVw(%)	CVB(%)
tmax (h)	1.84 (1.02-3.00)	2.01 (1.67-2.33)	27.4	13.9
Cmax (µmol/L)	15.2 (2.8)	15.7 (1.7)	9.2	11.7
AUC (µmol*h/L)	248 (62)	245 (65)	9.7	23.7
F	0.76 (0.11)	0.76 (0.11)	9.8	10.6
t1/2,z (h)	10.7 (2.88)	10.9 (3.70)	12.4	27.4

Values are expressed as mean (± s.d.) except t_max: median (range).

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): bioaccumulation potential cannot be judged based on study resultsQuinine had an absorption rate of 76 % after oral administration. The AUC was about 248 µmol/L *h. The half-life of quinine in plasma was about 10 hours.

Executive summary:

In the study published by Paintaud, 1993 the pharmacokinetic of quinine was determined after oral administration. Quinine had an absorption rate of 76 %. The AUC was about 248 µmol/L *h and the peak plasma concentration was about 15.2 µmol/L. The half-life of quinine in plasma was about 10 hours. It can be conclude that the oral absorption of quinine is extensive and fast in healthy subjects.