Europ.J.clin.Pharmacol. IO, 343-347 (1976) © by Springer-Verlag [976
Serum Concentrations of Methaqualone after Repeated Oral Doses of a Combination Formulation to Human Subjects C. White*, E. Doyle, L. F. Chasseaud and T. Taylor D e p a r t m e n t of M e t a b o l i s m Huntingdon, E n g l a n d Received: accepted:
December 29, May 20, 1976
and P h a r m a c o k i n e t i c s ,
1975,
and in r e v i s e d
Huntingdon
form:
March
5,
Research
Centre,
1976,
Summary. C o n c e n t r a t i o n s of m e t h a q u a l o n e have been m e a s u r e d in the serum of five male human subjects r e c e i v i n g five c o n s e c u t i v e e v e n i n g doses of a c o m b i n a t i o n formulation c o n t a i n i n g m e t h a q u a l o n e (250 mg), carbromal (300 mg) and b e n a c t y z i n e (0.33 mg) in each tablet. After a d m i n i s t r a t i o n of the first dose, mean peak serum c o n c e n t r a tions of m e t h a q u a l o n e (1.2 ~g/ml) o c c u r r e d at 3 h. After o b t a i n i n g peak levels, m e a n c o n c e n t r a t i o n s of m e t h a q u a l o n e d e c l i n e d rapidly d u r i n g the next 6 h and thereafter more s l o w l y d u r i n g the next 18 h. A f t e r a d m i n i s t r a t i o n of the last (fifth) dose, mean peak serum c o n c e n t r a t i o n s of m e t h a q u a l o n e (1.9 ~g/ml; 1.5 zg/ml above the p r e d o s e level) o c c u r r e d at 2 h. A f t e r a t t a i n i n g peak levels, mean c o n c e n t r a tions of m e t h a q u a l o n e d e c l i n e d r a p i d l y during the next 6 h, and thereafter more slowly, with a h a l f - l i f e of a p p r o x i m a t e l y 10 h. Mean c o n c e n t r a t i o n s of m e t h a q u a lone in serum samples 24 h after the second, third, fourth or fifth doses were not s i g n i f i c a n t l y d i f f e r e n t (0.3 ~g/ml - 0.6 ug/ml) d u r i n g this period of dosing. This suggests that s i g n i f i c a n t a c c u m u l a t i o n of m e t h a q u a l o n e in the serum did not occur d u r i n g a period of five c o n s e c u t i v e e v e n i n g doses of the c o m b i n a t i o n formulation. Key words: M e t h a q u a l o n e ,
hypnotic,
pharmacokinetics,
The s e d a t i v e - h y p n o t i c p r o p e r t i e s of methaqualone have been d e m o n s t r a t e d in several clinical studies (I - 4) and the o p t i m u m oral dosage is t h o u g h t to be about 300 mg (5). C o n s i d e r a b l e i n t e r e s t in the drug has r e s u l t e d in several reports of its pharm a c o k i n e t i c s and b i o a v a i l a b i l i t y (6 - 12) and its m e t a b o l i s m in humans has also been studied (13 - 16). In some of these studies, the drug appeared to be administered in the m o r n i n g after a period of fasting, c o n d i t i o n s g e n e r a l l y e m p l o y e d for b i o a v a i l a b i l i t y testing. The p r e s e n t
Present address: Darwin College, University of Cambridge, Cambridge, England
combination
formulation.
paper d e s c r i b e s serum c o n c e n t r a t i o n s of m e t h a q u a l o n e achieved after a d m i n i s t r a tion of the drug to n o n - f a s t i n g human subjects for five c o n s e c u t i v e evenings in a c o m m e r c i a l l y - a v a i l a b l e combination p r e p a r a t i o n c o n t a i n i n g m e t h a q u a l o n e (250 mg), c a r b r o m a l (300 mg) and b e n a c t y z i n e h y d r o c h l o r i d e (0.33 mg). EXPERIMENTAL Materials
The w h i t e tablet c o m b i n a t i o n f o r m u l a t i o n used in these studies was S t a u r o d o r m ® and was s u p p l i e d by D o l o r g i e t A r z n e i m i t telfabrik, Bad Godesberg, Germany. Glutethimide (internal standard) was a gift from Ciba L a b o r a t o r i e s Limited, Horsham, Sussex, England.
344 Methods
RESULTS
Five h e a l t h y adult male subjects within an age range of 29 - 39 years and a w e i g h t range of 66 - 83 kg and w i t h o u t histories of renal, hepatic, cardiac, endocrine, m e t a b o l i c or g a s t r o i n t e s t i n a l disorders, or known sensitivity to drugs, were c l i n i c a l l y e x a m i n e d during the week p r e c e d i n g the studies. Blood and urine samples were taken from the subjects for laboratory tests, the results of which were w i t h i n normal ranges. The haematology p a r a m e t e r s included haemoglobin, PCV, RBC, MCV, MCHC, ESR, WBC (and differential), platelets and reticulocytes. The b l o o d b i o c h e m i s t r y p a r a m e t e r s included urea, glucose, p r o t e i n (albumin and globulins), SAP, SGPT, SGOT, bilirubin, Na + and K +. The u r i n a l y s i s included protein, glucose and cells. After the aim of the studies and the nature of the drug had been explained, the subjects c o n s e n t e d to participate. No other medication, alcohol or smoking were p e r m i t t e d during the study period. The results of clinical e x a m i n a t i o n s repeated on completion of the studies did not differ s i g n i f i c a n t l y from predose values. The studies were carried out in Addenbrooke's Hospital and the D e p a r t m e n t of Medicine, U n i v e r s i t y of Cambridge, Cambridge. In the evening of the first day of administration, the subjects consumed a standard meal and two hours later, at 21.00 h, took one S t a u r o d o r m ® tablet together w i t h 50 - 100 ml water. Blood samples were w i t h d r a w n from the antecubital veins before dosing and at intervals thereafter. S i m i l a r i l y on each of the four following evenings, blood samples were w i t h d r a w n from each of the subjects at 2 h after the evening meal, at 24 h after the previous dose. Each subject was then a d m i n i s t e r e d one tablet of S t a u r o d o r m ®. No r e s t r i c t i o n s were placed upon food or a c t i v i t y d u r i n g the day. A d d i t i o n a l blood samples were taken following the fifth (and last) dose so as to d e f i n e the d e c l i n e of serum drug concentrations. I m m e d i a t e l y after withdrawal, blood samples were allowed to clot at O ° C. The serum was separated by c e n t r i f u g a t i o n and stored at -20 ° C. C o n c e n t r a t i o n s of m e t h a q u a l o n e in the serum were m e a s u r e d by the m e t h o d of Ber~ ry (17) except that g l u t e t h i m i d e was used as an internal standard (18). The method was specific for m e t h a q u a l o n e and the limit of d e t e c t i o n was O.1 ~g/ml serum. Recoveries of m e t h a q u a l o n e added to serum ranged b e t w e e n 90 % to 102 % (mean 93 %) and the p r e c i s i o n of the m e t h o d was 8 % (C.V.) at the c o n c e n t r a t i o n s measured. Standard curves were c o n s t r u c t e d from m e a s u r e m e n t s of m e t h a q u a l o n e added to serum so as to a u t o m a t i c a l l y c o r r e c t for any small losses in analysis.
A f t e r doses of a single m e t h a q u a l o n e c o n t a i n i n g tablet (Staurodorm ®) on the first day of administration, peak conc e n t r a t i o n s of m e t h a q u a l o n e w e r e m e a s u r e d at 2 h in two subjects (1.8 ~g/ml and 1.0 zg/ml respectively), at 3 h in two subjects (1.4 zg/ml and 1.2 ~g/ml respectively), and at 5 h in one subject (1.4 ~g/ml). M e t h a q u a l o n e was not d e t e c t e d in the serum of subject no. 3 until 2 h after dosing. The peak of m e a n serum conc e n t r a t i o n s of 1.2 ~g/ml o c c u r r e d at 3 h and declined fairly rapidly d u r i n g the next 4 to 5 h, and t h e r e a f t e r more slowly until at 24 h, a m e a n c o n c e n t r a t i o n of 0.3 ~g/ml was m e a s u r e d (Table I). Mean serum c o n c e n t r a t i o n s of m e t h a q u a l o n e in samples w i t h d r a w n during the second, third, fourth and fifth days of a d m i n i s t r a t i o n ranged b e t w e e n 0.3 ~g/ml and 0.6 ~g/ml and the c o n c e n t r a t i o n s were not s i g n i f i c a n t l y d i f f e r e n t as shown by an analysis of variance. These samples were w i t h d r a w n 24 h after the previous dose, and i m m e d i a t e l y before the next evening dose, and c o n c e n t r a t i o n s of methaqualone did not increase s i g n i f i c a n t l y w i t h the number of doses administered. Thus there was little evidence of accumulation of m e t h a q u a l o n e in Serum after repeated doses of 250 mg of m e t h a q u a l o n e in the c o m b i n a t i o n formulation of Staurodorm ® a d m i n i s t e r e d at 24 h intervals d u r i n g 5 days. C o n c e n t r a t i o n s of methaqualone in the serum of subject no. 2 (Table I) were b e l o w the limits of detection 24 h after the first, third and fourth doses. After the last dose, peak serum conc e n t r a t i o n s of m e t h a q u a l o n e were detected at 3 h in two subjects (3.2 ~g/ml and 2.0 ~g/ml respectively), at I h in two subjects (3.6 ~g/ml and 1.8 ~g/ml respectively), but peak levels were not detected in the serum of one subject (1.9 ~g/ ml) until 7 h after dosing. The peak of mean serum c o n c e n t r a t i o n s of 1.9 ~g/ml was reached at 2 h after dosing (1.5 ~g/ ml above the predose value). The peak of mean serum c o n c e n t r a t i o n s of m e t h a q u a l o n e after the fifth dose (1.9 ~g/ml) was app a r e n t l y higher than after the first dose (1.2 Dg/ml) (Figure I), but statistical analysis (t-test) showed that this difference was not s i g n i f i c a n t (P > 0.05). Peak serum c o n c e n t r a t i o n s of m e t h a q u a i o n e d e t e c t e d on the fifth and last day of dosing, w h e n c o r r e c t e d for p r e d o s e values, were similar to those m e a s u r e d after the first day of dosing. After reaching peak values, mean c o n c e n t r a t i o n s d e c l i n e d d u r i n g the next 6 h, and t h e r e a f t e r more slowly, with a h a l f - l i f e of a p p r o x i m a t e l y 10 h, m e a s u r e d b e t w e e n 8 h and 48 h after a d m i n i s t r a t i o n of the last dose (Fig. I). I n s u f f i c i e n t samples were w i t h d r a w n after a d m i n i s t r a t i o n of the first dose
345 Table I. Serum concentrations of metk~aqualone after repeated administration of a combination formulation containing methaqualone (250 mg), carbromal (300 mg) and benactyzine (0.33 mg), to five male human subjects. The subjects each received one tablet each evening for five consecutive evenings (i.e. at O, 24, 48, 72 and 96 h) Serum concentrations of methaqualone Time (h)
Predose
0.5
1
2
3
5
7
24
48
96.5
96
72
97
98
(zg/ml) 99
132
101 103 120
144
Subject no.
1 2 3 4 5 Subject meal]
Serum Concentrations of Methaqualone after Repeated Oral Doses of a Combination Formulation to Human Subjects C. White*, E. Doyle, L. F. Chasseaud and T. Taylor D e p a r t m e n t of M e t a b o l i s m Huntingdon, E n g l a n d Received: accepted:
December 29, May 20, 1976
and P h a r m a c o k i n e t i c s ,
1975,
and in r e v i s e d
Huntingdon
form:
March
5,
Research
Centre,
1976,
Summary. C o n c e n t r a t i o n s of m e t h a q u a l o n e have been m e a s u r e d in the serum of five male human subjects r e c e i v i n g five c o n s e c u t i v e e v e n i n g doses of a c o m b i n a t i o n formulation c o n t a i n i n g m e t h a q u a l o n e (250 mg), carbromal (300 mg) and b e n a c t y z i n e (0.33 mg) in each tablet. After a d m i n i s t r a t i o n of the first dose, mean peak serum c o n c e n t r a tions of m e t h a q u a l o n e (1.2 ~g/ml) o c c u r r e d at 3 h. After o b t a i n i n g peak levels, m e a n c o n c e n t r a t i o n s of m e t h a q u a l o n e d e c l i n e d rapidly d u r i n g the next 6 h and thereafter more s l o w l y d u r i n g the next 18 h. A f t e r a d m i n i s t r a t i o n of the last (fifth) dose, mean peak serum c o n c e n t r a t i o n s of m e t h a q u a l o n e (1.9 ~g/ml; 1.5 zg/ml above the p r e d o s e level) o c c u r r e d at 2 h. A f t e r a t t a i n i n g peak levels, mean c o n c e n t r a tions of m e t h a q u a l o n e d e c l i n e d r a p i d l y during the next 6 h, and thereafter more slowly, with a h a l f - l i f e of a p p r o x i m a t e l y 10 h. Mean c o n c e n t r a t i o n s of m e t h a q u a lone in serum samples 24 h after the second, third, fourth or fifth doses were not s i g n i f i c a n t l y d i f f e r e n t (0.3 ~g/ml - 0.6 ug/ml) d u r i n g this period of dosing. This suggests that s i g n i f i c a n t a c c u m u l a t i o n of m e t h a q u a l o n e in the serum did not occur d u r i n g a period of five c o n s e c u t i v e e v e n i n g doses of the c o m b i n a t i o n formulation. Key words: M e t h a q u a l o n e ,
hypnotic,
pharmacokinetics,
The s e d a t i v e - h y p n o t i c p r o p e r t i e s of methaqualone have been d e m o n s t r a t e d in several clinical studies (I - 4) and the o p t i m u m oral dosage is t h o u g h t to be about 300 mg (5). C o n s i d e r a b l e i n t e r e s t in the drug has r e s u l t e d in several reports of its pharm a c o k i n e t i c s and b i o a v a i l a b i l i t y (6 - 12) and its m e t a b o l i s m in humans has also been studied (13 - 16). In some of these studies, the drug appeared to be administered in the m o r n i n g after a period of fasting, c o n d i t i o n s g e n e r a l l y e m p l o y e d for b i o a v a i l a b i l i t y testing. The p r e s e n t
Present address: Darwin College, University of Cambridge, Cambridge, England
combination
formulation.
paper d e s c r i b e s serum c o n c e n t r a t i o n s of m e t h a q u a l o n e achieved after a d m i n i s t r a tion of the drug to n o n - f a s t i n g human subjects for five c o n s e c u t i v e evenings in a c o m m e r c i a l l y - a v a i l a b l e combination p r e p a r a t i o n c o n t a i n i n g m e t h a q u a l o n e (250 mg), c a r b r o m a l (300 mg) and b e n a c t y z i n e h y d r o c h l o r i d e (0.33 mg). EXPERIMENTAL Materials
The w h i t e tablet c o m b i n a t i o n f o r m u l a t i o n used in these studies was S t a u r o d o r m ® and was s u p p l i e d by D o l o r g i e t A r z n e i m i t telfabrik, Bad Godesberg, Germany. Glutethimide (internal standard) was a gift from Ciba L a b o r a t o r i e s Limited, Horsham, Sussex, England.
344 Methods
RESULTS
Five h e a l t h y adult male subjects within an age range of 29 - 39 years and a w e i g h t range of 66 - 83 kg and w i t h o u t histories of renal, hepatic, cardiac, endocrine, m e t a b o l i c or g a s t r o i n t e s t i n a l disorders, or known sensitivity to drugs, were c l i n i c a l l y e x a m i n e d during the week p r e c e d i n g the studies. Blood and urine samples were taken from the subjects for laboratory tests, the results of which were w i t h i n normal ranges. The haematology p a r a m e t e r s included haemoglobin, PCV, RBC, MCV, MCHC, ESR, WBC (and differential), platelets and reticulocytes. The b l o o d b i o c h e m i s t r y p a r a m e t e r s included urea, glucose, p r o t e i n (albumin and globulins), SAP, SGPT, SGOT, bilirubin, Na + and K +. The u r i n a l y s i s included protein, glucose and cells. After the aim of the studies and the nature of the drug had been explained, the subjects c o n s e n t e d to participate. No other medication, alcohol or smoking were p e r m i t t e d during the study period. The results of clinical e x a m i n a t i o n s repeated on completion of the studies did not differ s i g n i f i c a n t l y from predose values. The studies were carried out in Addenbrooke's Hospital and the D e p a r t m e n t of Medicine, U n i v e r s i t y of Cambridge, Cambridge. In the evening of the first day of administration, the subjects consumed a standard meal and two hours later, at 21.00 h, took one S t a u r o d o r m ® tablet together w i t h 50 - 100 ml water. Blood samples were w i t h d r a w n from the antecubital veins before dosing and at intervals thereafter. S i m i l a r i l y on each of the four following evenings, blood samples were w i t h d r a w n from each of the subjects at 2 h after the evening meal, at 24 h after the previous dose. Each subject was then a d m i n i s t e r e d one tablet of S t a u r o d o r m ®. No r e s t r i c t i o n s were placed upon food or a c t i v i t y d u r i n g the day. A d d i t i o n a l blood samples were taken following the fifth (and last) dose so as to d e f i n e the d e c l i n e of serum drug concentrations. I m m e d i a t e l y after withdrawal, blood samples were allowed to clot at O ° C. The serum was separated by c e n t r i f u g a t i o n and stored at -20 ° C. C o n c e n t r a t i o n s of m e t h a q u a l o n e in the serum were m e a s u r e d by the m e t h o d of Ber~ ry (17) except that g l u t e t h i m i d e was used as an internal standard (18). The method was specific for m e t h a q u a l o n e and the limit of d e t e c t i o n was O.1 ~g/ml serum. Recoveries of m e t h a q u a l o n e added to serum ranged b e t w e e n 90 % to 102 % (mean 93 %) and the p r e c i s i o n of the m e t h o d was 8 % (C.V.) at the c o n c e n t r a t i o n s measured. Standard curves were c o n s t r u c t e d from m e a s u r e m e n t s of m e t h a q u a l o n e added to serum so as to a u t o m a t i c a l l y c o r r e c t for any small losses in analysis.
A f t e r doses of a single m e t h a q u a l o n e c o n t a i n i n g tablet (Staurodorm ®) on the first day of administration, peak conc e n t r a t i o n s of m e t h a q u a l o n e w e r e m e a s u r e d at 2 h in two subjects (1.8 ~g/ml and 1.0 zg/ml respectively), at 3 h in two subjects (1.4 zg/ml and 1.2 ~g/ml respectively), and at 5 h in one subject (1.4 ~g/ml). M e t h a q u a l o n e was not d e t e c t e d in the serum of subject no. 3 until 2 h after dosing. The peak of m e a n serum conc e n t r a t i o n s of 1.2 ~g/ml o c c u r r e d at 3 h and declined fairly rapidly d u r i n g the next 4 to 5 h, and t h e r e a f t e r more slowly until at 24 h, a m e a n c o n c e n t r a t i o n of 0.3 ~g/ml was m e a s u r e d (Table I). Mean serum c o n c e n t r a t i o n s of m e t h a q u a l o n e in samples w i t h d r a w n during the second, third, fourth and fifth days of a d m i n i s t r a t i o n ranged b e t w e e n 0.3 ~g/ml and 0.6 ~g/ml and the c o n c e n t r a t i o n s were not s i g n i f i c a n t l y d i f f e r e n t as shown by an analysis of variance. These samples were w i t h d r a w n 24 h after the previous dose, and i m m e d i a t e l y before the next evening dose, and c o n c e n t r a t i o n s of methaqualone did not increase s i g n i f i c a n t l y w i t h the number of doses administered. Thus there was little evidence of accumulation of m e t h a q u a l o n e in Serum after repeated doses of 250 mg of m e t h a q u a l o n e in the c o m b i n a t i o n formulation of Staurodorm ® a d m i n i s t e r e d at 24 h intervals d u r i n g 5 days. C o n c e n t r a t i o n s of methaqualone in the serum of subject no. 2 (Table I) were b e l o w the limits of detection 24 h after the first, third and fourth doses. After the last dose, peak serum conc e n t r a t i o n s of m e t h a q u a l o n e were detected at 3 h in two subjects (3.2 ~g/ml and 2.0 ~g/ml respectively), at I h in two subjects (3.6 ~g/ml and 1.8 ~g/ml respectively), but peak levels were not detected in the serum of one subject (1.9 ~g/ ml) until 7 h after dosing. The peak of mean serum c o n c e n t r a t i o n s of 1.9 ~g/ml was reached at 2 h after dosing (1.5 ~g/ ml above the predose value). The peak of mean serum c o n c e n t r a t i o n s of m e t h a q u a l o n e after the fifth dose (1.9 ~g/ml) was app a r e n t l y higher than after the first dose (1.2 Dg/ml) (Figure I), but statistical analysis (t-test) showed that this difference was not s i g n i f i c a n t (P > 0.05). Peak serum c o n c e n t r a t i o n s of m e t h a q u a i o n e d e t e c t e d on the fifth and last day of dosing, w h e n c o r r e c t e d for p r e d o s e values, were similar to those m e a s u r e d after the first day of dosing. After reaching peak values, mean c o n c e n t r a t i o n s d e c l i n e d d u r i n g the next 6 h, and t h e r e a f t e r more slowly, with a h a l f - l i f e of a p p r o x i m a t e l y 10 h, m e a s u r e d b e t w e e n 8 h and 48 h after a d m i n i s t r a t i o n of the last dose (Fig. I). I n s u f f i c i e n t samples were w i t h d r a w n after a d m i n i s t r a t i o n of the first dose
345 Table I. Serum concentrations of metk~aqualone after repeated administration of a combination formulation containing methaqualone (250 mg), carbromal (300 mg) and benactyzine (0.33 mg), to five male human subjects. The subjects each received one tablet each evening for five consecutive evenings (i.e. at O, 24, 48, 72 and 96 h) Serum concentrations of methaqualone Time (h)
Predose
0.5
1
2
3
5
7
24
48
96.5
96
72
97
98
(zg/ml) 99
132
101 103 120
144
Subject no.
1 2 3 4 5 Subject meal]
