Journal o[- Pharmacokinetics and Biopharmaceutics, Vol. 2, No. 3, 1974

Half-life of Diphenylpyraline in Man

G. Graham l"z and A. G. Bolt 1.3

Received Aug. I0, 1973- Final Mar. 11, 1974

The biological ha!f-life o[" diphenylpyraline was determined in five healthy subjects from the urinary excretion of the unchanged drug. Hall-lives ranged from 24 to 40 hr.

KEY WORDS: gas chromatographic assay of diphenylpyraline; urinary excretion; half-life of diphenylpyraline.

Although diphenylpyraline [4-(diphenyl-methoxy)-l-methyl piperidine] has been used for several years as an antihistamine, no details of its rate of metabolism or excretion have been published. No assay has been developed for the low levels of the drug in plasma following the usual therapeutic doses (2T5 mg). However, the gas chromatographic procedure described in the presen~ communication is sufficiently sensitive to determine the levels of diphenylpyraline in urine, and the biological half-life of diphenylpyraline has been determined from the excretion of the unchanged drug.

The urinary excretion of bases is usually dependent on urinary pH. However, Rowland (1) showed that the half-life of amphetamine could be determined from urinary excretion data without control of urinary pH. Urine samples were collected over long time intervals (12 hr), thus mini- mizing variations in urinary pH and hence fluctuations in the rate of elim- ination of amphetamine. The biological half-life of diphenylpyraline has also proved sufficiently long to be determined from levels of the unchanged drug in 12 hourly urine collections.

1Riker Laboratories Australia Pry. Ltd., Hornsby, New South Wales 2077, Australia. ZPresent address: Department of Clinical Pharmacology, St. Vincent's Hospital, Darlinghurst, New South Wales 2010, Australia.

3present address: Raymond Purves Research Laboratories, Royal North Shore Hospital, St. Leonards, New South Wales, Australia.

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�9 1974 Plenum Publishing Corporation, 227 West 17th Street, New York, N.Y. 10011. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, microfilming, recording, or otherwise, without written permission of the publisher.

192 Graham and Bolt

Diphenylpyraline hydrochloride (2 • 2.5 mg Histalert tablets, Riker Laboratories, Australia) was administered to five healthy male subjects, aged 25-35 years. The dose was administered at least 1�89 after a light breakfast. The subjects were not receiving any other drugs. Urine was collected at 12 hour intervals for 5 days and stored at - 2 0 ~ until assayed. Duplicate aliquots of urine (25-50 ml) containing lignocaine (50 #g) as the internal standard were rendered alkaline with 10N sodium hydroxide (2 ml) and extracted with 1 ~o isoamyl alcohol in ether (25 ml) by shaking for 5 min. The organic phase was 'extracted with 1 N hydrochloric acid (5 ml) by shaking for 3 min. The aqueous phase was washed with isoamyl alcohol-ether (1.5 ml), rendered alkaline with 10 N sodium hydroxide (1 ml), and extracted with isoamyl alcohol-ether (3 ml) by shaking for 3 min. The phases separated cleanly after centrifugation at each extraction step and the required phases were removed as completely as possible. The final extract

1 0 0 -

0 o

A

I I

I ! 0 5

13

I 1 0

TIME, min

Fig. 1. Gas chromatogram of urine extract containing ligno- caine (A) as the internal stand- ard and diphenylpyraline (B). Sensitivity changed at arrow from 10 -9 to 10-1~ full- scale deflection.

Half-life of Diphenylpyraline in Man t93

was allowed to evaporate below 40~ to a volume of 12 15 #1. Aliquots of the remaining solutions were analyzed using a Packard gas chromatograph, series 7800, equipped with a flame ionization detector. The glass column (190 by 0.4 cm I D) was packed with 2 ~o Carbowax 20M and 5 ~o potassium hydroxide on Chromosorb WHMDS, 100-120 mesh. The column was main- tained at 200~ while the inlet and detector temperatures were 215 and 212~ respectively. Gas flows were as follows: nitrogen, 50 ml/min; hydro- gen, 60ml/min; air, 250ml/min. The columns were conditioned at the settings listed above for 48 hr before use. The coefficients of variation of peak height ratios from replicate solutions ranged from 1 to 4~o. A typical chromatogram is shown in Fig. 1. No compounds with retention times similar to that of lignocaine or diphenylpyraline were observed in extracts of urine collected before dosage with diphenylpyraline.

The biological half-life (tl/2) of diphenylpyraline was calculated both from the cumulative urinary excretion of unchanged drug by the method of Guggenheim (2) and from semilogarithmic plots of the rate of excretion vs. time. Similar values were found from the two procedures. Half-lives cal- culated by the Guggenheim method ranged from 24 to 40 hr (Table I). In the present case, the Guggenheim method involved the regression analysis of the relationship between ln(Ae(6o+t ) -Ae(t) ) and t, where Ae(6O+t ) and Ae(t) are the cumulative amounts of unchanged drug excreted at 60 + t and t hr after dosage. This procedure is valid only for monoexponential functions. The absorption processes must make the excretion of diphenylpyraline a more complex function during the first collection period, and the biological half-life was calculated using values of t in the range 12-60 hr. Results from a representative subject plotted by the Guggenheim procedure are shown in Fig. 2. The agreement between the experimental points and the regression line is good, consistent with first-order elimination of diphenylpyraline.

The total amount of diphenylpyraline excreted unchanged, Ae(~), was estimated from the relationship below, a method analogous to that used by Beckett and Rowland (3):

Ae(,:,o) = Ae(12) + Ae(12o_12) / ( l - e lo8k)

Table I. Parameters of the Urinary Excretion of Diphenylpyraline Following Oral Dosage

Subject Weight Percent of dose excreted Half-life ( k g ) unchanged, A~(~) (hr)

1 77 6.8 26 2 63 3.6 39 3 76 9.3 24 4 83 2.3 30 5 75 4.1 40

194 Graham and Bolt

0.3

~ 0 . 2

< P

+

o CD

"$ 0.1 <

0o , 10 go do TIME, hours

Fig. 2. Guggenheim plot. Difference between cumulative excretion at 60 + t and t hr (Ae(6o+,) - Ae(o) plotted vs. time. Point at zero time excluded from regression analysis as described in the text.

w h e r e Ae(12 ) is the amount of diphenylpyraline excreted up to 12 hr after d o s a g e , Ae(120_121 is the amount of diphenylpyraline excreted between 12 and 120 hr after dosage, and k is the apparent rate constant of elimination (0.693/t~/2). The calculated values of Ae(oo) are shown in Table I. Clearly, only small fractions of the oral doses of diphenylpyraline were excreted unchanged.

The half-life of diphenylpyraline is long, and significant accumulation is anticipated on continuous dosage at the recommended schedules (2-5 mg three times daily). Accumulation over the first few days of continuous therapy may be expected to lead to an increasing incidence of side-effects during this time. However, this pattern of incidence of side-effects has not been described. Possibly, accumulation does not lead to adverse reactions owing to the development of tolerance to the side-effects, a well-known phenomenon of continuing antihistamine therapy (4). Nevertheless, the long half-life of diphenylpyraline should be considered in the further develop- ment of optimal dosage schedules.

REFERENCES

1. M. Rowland. Amphetamine blood and urine levels in man. J. Pharm. Sci. 58" 508-509 (1969). 2. E. A. Guggenheim. On the determination of the velocity constant o fa unimolecular reaction. Phil. Mag. 2:538-543 (1926).

Half-life of Diphenylpyraline in Man |9S

3. A. H. Beckett and M. Rowland. Urinary excretion kinetics of amphetamine in man. J. Pharm. Pharmacol. 17:628-639 (1965).

4. W. W. Douglas. Histamine and antihistamines; 5-hydroxytryptamine and antagonists. In L. S. Goodman and A. Gilman (eds.), The Pharmacological Basis of Therapeutics, Mac- millan, New York, 1970, pp. 621-662.