Potgieter, F.J.

Van Oudtshoorn, M.C.B.

English

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1384LCM 106S.A. MEDICAL JOURNAL(Supplement-SOlllh African Journal of Laboratory and Clinical Medicine)8 overnber 1969STUDIES ON THE CRYSTALLURIA POTENTIAL OF SULPHONAMIDES: ACETYLATIONOF SULPHADIMIDINE UNDER CONTROLLED ALKALINE URINE CONDITIONSF. J. POTGIETER AND M. C. B. VAN OUDTSHOORN, Department of Pharmaceutics, Po/chefs/room University,Po/chefs/room, Tv!The kinetics of absorption, metabolism and excretion ofsulphonamides have been studied by examination of bloodand, in certain cases, urine.'" Studies on the acetylationof sulphafurazole' and sulphamethylthiadiazole3 in humantest subjects indicate that excretion of the acetylated drugis the terminal step in a two-step consecutive first-orderprocess Qf which the first step is acetylation. This wasalso shown to be the case for sulphadimidine.'Although the metabolism of sulphonamides is discussedin standard textbooks, no attention is given to the factthat the acetylation of sulphadimidine by man exhibitsgenetic polymorphism.' It was shown that there are tworecognizable phenotypes, namely, rapid and slow acety-la tors, and that slow acetylation is a Mendelian-recessivecharacter. In a recent publicaton we have described thekinetic parameters for absorption and excretion of rapidand slow acetylators of sulphadimidine:The work reported now was conducted as part of aprogramme on the evaluation of various pharmaceuticaldosage forms of sulphadimidine. The possibility of theoccurrence of crystalluria in the therapy with sulphona-mides should always be considered, since its consequencesmay be quite serious if precipitation of the drug occursin the kidney.METHODSA test panel of 4 healthy young male adults was used inthe study; 1·0 G sulphadimidine in the form of two com-pressed tablets was ingested in the morning on stomachsthat had been fasted overnight. No food was taken until2 hours after ingestion of the dose. Sufficient water wastaken to maintain an adequate urine flow. After drugingestion quantitative urine collections were obtained atintervals as shown in Table I. Free and total sulphona-mide concentrations in urine were estimated by the Brat-ton-MarshalI' procedure. Alkaline urine conditions weremaintained with an alkali load of 2·0 G of sodium bi-carbonate every 3 hours.RESULTS AND DISCUSSIONThe mInImum urine flow-rate needed to prevent the oc-currence of cry talluria may be calculated by the followingexpression.'Minimum flow-rate = Excretion rate/Solubility.In this expression excretion rate refers to the acetylsul-phadimidine expected to precipitate and is taken to bein units of mg./hr. If solubility is taken in units of mg./mJ., then minimum flow-rate will be in units of mI./hr.·The solubility of acetylsulphadimidine at pH 7 and 37"Cwas taken as 1-45 mg. / mJ.'oThe minimum flow-rates calculated using the aboveexpression for the 4 test subjects are given in Table I.Using the method described by White and Evans,"subject C was phenotyped as a rapid acetylator of sulpha-dimidine with an acetylation of more than 80o~. Fromthe results in Table I it can be seen that the excretion rateof acetylated drug for subject C is considerably higherthan for the other 3 test subjects; a much higher urineflow-rate is also necessary.At a dose level of 3·0 G, which is recommended as theinitial dose for sulphadimidine, a much higher urine flow-rate is necessary and a much higher excretion rate of ace-tylated drug can be expected. Special attention should begiven to the urine flow-rate of a rapid acetylator of sul-phadimidine even under controlled alkaline urineconditions.SUMMARYUsing a single oral dose of 1-0 G of sulphadimidine as 2 com-pressed tablets, different concentrations of acetylsulphadimidinewere recovered in the urine after 48 hours. One test subjectwas phenotyped as a rapid acetylator of sulphadimidine withan acetylation of more than 80%. The minimum urine flow-rate needed to prevent the occurrence of crystalluria due toprecipitation of 'N acetylated drug is calculated for 4 testsubjects.This study was supported by a research grant from the CSIR.REFERENCES1. Nelson, E. and Schaldemose, 1. (959): J. Amer. Pharm. Assoc .. 48,4 '9.2. Nelson, E. and O'Reilly, 1. (1960): J. Pharmacol. Exp. Ther.. 129, 368.3. Idem (1961): J. Pharm. Sci .. SO, 417.4. Turco. G. L., De Filippi, P.. Prinetti, V. and Segre. G. (1966): Clin.Pharmacol. Ther., 7. 603.5. Van Oudtshoorn. M. C. B. and Potgieler. F. J. (1969): E.• perientia(Base!) (in the press).6. White. T. A. and Evans. D. A. P. (1964): J. Lab. Clin. Med .. 63, 394.7. Bratton, A. C. and MarshaIl. E. K. (1939): J. BioI. Chem.. 128. 537.8. Nelson. E. (1961): 'alure (Lond.). 189. 928.9. Idem (1965/1966): Chemotherapia (Base!). 10. 145.10. Kruger-Thiemer. E. and Bunger, P. (1961): Arzneimittel-Forsch .. 11,67.11. White. T. A. and Evans, D. A. P. (1968): Clin. Pharmacol. Ther., 9,80.TABLE J. MINIMUM URINE FLOW-RATE NECESSARY TO PREVENT CRYSTALL RIA FOLLOWING 1· O-G ORAL DOSE OF SULPHADIMIDINE AT pH 7Excrerioll rate of acetylaied drug (mg./hr) Flow-rate (ml.jllr)TimeSubjecr Subject Subject Subject Subject Subject Subject SubjectA B C D A B C D0-1 4·1 0 7·6 0 2·8 0 5·2 01-2 6·6 6·2 45·9 2·0 4·5 4·3 31·7 1·42-3 15·1 14·0 79·8 11·2 10·4 9·7 55·0 7·73-4 12·2 15·9 77·7 14·7 8·4 11·0 53·6 10·14-5 14·8 21·2 83·5 24·7 10·2 14·6 57·6 17·05-6 22·6 16·5 ·2 22· 15·6 11·3 53·9 15·76-9 17·7 24·4 61 ·7 31·9 12·2 16·8 42·6 22·09-12 23·6 29·3 46·4 0·9 16·3 20·2 32·0 0·612-24 13·0 11·1 8'5 13·3 9·0 7·7 5·9 9·224-36 9,' 7·1 2·3 4,' 6·3 4·9 1·6 2·836-4 2·8 ],2 0'5 0·1 1·9 0·8 C·3 0,]% acetylation 64'8% 61'8% 86'90% 66'3%

Studies on the crystalluria potential of sulphonamides: Acetylation of sulphadinidine under controlled alkaline urine conditions

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Studies on the crystalluria potential of sulphonamides: Acetylation of sulphadinidine under controlled alkaline urine conditions

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