Summary

Original Researcb Article

Clinical Pharmacokinetics 16: 317-325 (1989) 0312-5963/89/0005-0317/$04.50/0 © ADIS Press Limited All rights reserved.

Co-Trimoxazole (Sulphamethoxazole plus Trimethoprim) Peritoneal Barrier Transfer Pharmacokinetics

Joseph E. Svirbely, Amadeo J. Pesce, Satwant Singh and Ellen J. O'Flaherty Department of Pathology and Laboratory Medicine, University of Cincinnati Medical Center, Hemodialysis Unit, Veterans Administration Medical Center, and Department of Environmental Health, University of Cincinnati Medical Center, Cincinnati, Ohio, USA

The pharmacokinetics of co·trimoxazole (sulphamethoxazole plus trimethoprim) were studied in end·stage renal disease in patients undergoing treatment with continuous am­bulatory peritoneal dialysis (CAPD) and free of peritonitis. Plasma and dialysate concen­trations were monitored for / exchange after administration of a single oral or intra­peritoneal dose of co-trimoxazole, and were filled by a pharmacokinetic model that took into account the equilibrium nature ofCAPD by including return/rom the peritoneum in oral studies and from the plasma in intraperitoneal studies. Clearances were calculated and compared by analysis of variance. There was a significant effect of direction of flow (p < 0.0/). plasma-peritoneal clearances being larger than peritoneal-plasma clearances for both drugs. In addition. there was a significant difference (p < 0.000/) between sul­phamethoxazole clearances and trimethoprim clearances. with the laller being greater in both directions.

Continuous ambulatory peritoneal dialysis (CAPO) [Popovich et al. 1976) has become an ac­cepted treatment for end-stage renal disease, de­spite the incidence of peritonitis which is a major complication and requires aggressive treatment with antibiotics. However, the latter, like many other drugs, display different characteristics in renal fail­ure patients treated with CAPO from those in healthy subjects (Maher 1984).

and measuring blood and dialysate concentrations over time, concluded that drug transfer from di­alysate to blood was rapid and extensive, while re­verse transfer was negligible. In contrast, Pancorbo and Comty (1981) calculated a plasma-to-dialysate clearance for gentamicin of 0.176 Llh after intra­peritoneal administration. The pharmacokinetics of tobramycin (Bunke et al. 1983a), vancomycin (Blevins et al. 1984; Pancorbo & Comty 1982) and several cephalosporins (Bunke et al. 1983b; Gross et al. 1983; Local et al. 1981) have also been stud­ied.

The pharmacokinetics of several antibiotics have been studied in CAPO. These studies, using a variety of approaches, have arrived at different conclusions regarding peritoneal transfer. Somani et al. (1982), administering gentamicin either in­traperitoneally or intravenously to CAPO subjects

Peritoneal transfer processes (Maher 1980) and the resistances that limited their rates (Dedrick et al. 1982; Nolph et al. 1980) have been identified

Peritoneal Barrier Pharmacokinetics

and characterised. Transfer across the peritoneal barrier occurs by both diffusion and ultrafiltration. Diffusion is the more rapid of the two, and is de­pendent on the area and permeability of the peri­toneal barrier and on the free concentrations of sol­ute in dialysate and in blood. Capillary permeability is inversely proportional to the square root of the molecular weight of the solute, and the distributed model of peritoneal transfer proposed by Flessner et al. (1984) leads to the expectation that this will also be true of the permeability of the peritoneal barrier. Permeability can also be expected to be in­fluenced by the polarity of the solute. Lipophilic chemicals are transferred rapidly across lipoid bar­riers by diffusion, while polar or ionised solutes are hindered in their passage by interactions with charged elements within the barrier (Maher 1980) and the fact that ionised compounds are less lipo­philic than their uncharged counterparts. If the peritoneal barrier were sufficiently impermeable to the ionised form of a solute, ionisation could in principle negate the availability of the solute for the diffusion process. Similarly, protein binding af­fects both diffusion and ultrafiltration, because bound drug is not available to either process due to the size of the drug-protein complex.

The purpose of this study is to define more clearly the importance of some of the parameters that influence drug transfer across the human peri­toneal barrier. Transfers from plasma to perito­neum and from peritoneum to plasma were mo­delled within 1 exchange. The effect of partition coefficient and degree of ionisation on peritoneal transfer processes was investigated, in order to es­tablish whether these factors influence transfer across the peritoneal barrier as they do that across other physiological barriers such as the blood-brain barrier and the transplacental barrier.

Co-trimoxazole (sulphamethoxazole plus tri­methoprim) was chosen because the molecular weights and protein binding characteristics after 2 days are similar, while their pKa values, classifi­cation as acidic or basic drug, and partition coef­ficients are different. This allowed determination of the effect of these latter factors on transfer across the peritoneal barrier while molecular size and pro-

318

tein binding were controlled. The pharmacokinet­ics of co-trimoxazole in CAPO have been inves­tigated before (Halstenson et al. 1984; Singlas et al. 1981), but the factors influencing peritoneal barrier transfer behaviour have not been previously de­scribed.

Plltients lind Methods

The pharmacokinetics of co-trimoxazole were studied following oral (PO) and intraperitoneal (IP) administration. Five adult male patients under­going CAPO for end-stage renal disease were en­rolled in the study, and 3 of these were the subject of the IP study. The patients were free of periton­itis both during and between studies. Experiments were monitored by the University of Cincinnati Committee on Human Research.

Before the PO study commenced, the overnight dialysate bag was drained, and vital signs were re­corded. Fresh dialysate (2L, 1.5% dextrose) was in­stilled into the peritoneum and zero-time blood and dialysate samples were drawn immediately before 1 co-trimoxazole tablet containing sulphamethox­azole 800mg plus trimethoprim 160mg ('Bactrim­OS') was administered (study time zero). Dialysate and blood were sampled at 0.25, 0.5, 1, 1.5, 2, 4, 6, 12, 24 and 48 hours. Dialysate was exchanged after 6 hours and every 4 to 6 hours thereafter.

For the IP study, co-trimoxazole (sulphame­thoxazole 800mg plus trimethoprim 160mg) ['Bac­trim IV'] was added to fresh dialysate, and the con­tents of the bag were mixed. Zero-time blood and dialysate were drawn and dialysate containing co­trimoxazole was instilled into the peritoneum. Ser­ial blood and dialysate samples were collected at 3 hours and the 48-hour samples were collected as in the PO study, except that additional samples were collected at 3 hours and the 48-hour samples were omitted. The first dialysate bag was ex­changed for fresh dialysate free of co-trimoxazole after 6 hours, and no further drug was given. Patients received no other medications during the study.

Analysis

Concentrations of sulphamethoxazole, N-ace­tylsulphamethoxazole, and trimethoprim were

Peritoneal Barrier Pharmacokinetics

tested in each sample. It should be noted that all patients studied were anuric during the course of the studies, making determination ofthe renal out­put of sulphamethoxazole and trimethoprim un­necessary. In order to calculate the percentage pro­tein binding free sulphamethoxazole was measured in each plasma sample by splitting the sample and separating free from bound drug using the Amicon Micropartition System (Amicon Corporation, Danvers, Massachusetts).

Concentrations of free and total sulphamethox­azole and N-acetylsulphamethoxazole in plasma and dialysate were measured by a spectrophoto­metric method (Bratton & Marshall 1939). The sensitivity of the Bratton-Marshall procedure in this laboratory is I mg/L, linearity is to 500 mg/L, and the patients were kept free of substances which could interfere, such as other sulpha drugs. Fur­thermore, each run included a zero-time sample as a patient blank. With regard to reproducibility, a 50 mg/L spiked control run together with patient runs between January and·May 1988, by 2 different technicians, yielded 29 control values with a mean of 46.6 ± 3.5 mg/L, with a coefficient of variation of 7.5%. A control was run with each batch of total sulphamethoxazole, free sulphamethoxazole, or N­acetylsulphamethoxazole during the study. Al­though hydroxysulphamethoxazole metabolites are theoretically capable of interfering with the Brat­ton-Marshall assay, concentrations are negligible during the first 6 hours after administration of an initial dose of sulphamethoxazole (Martea et al. 1987).

Trimethoprim concentrations in plasma and di­alysate were measured by a high performance li­quid chromatography (HPLC) method for tri­methoprim developed in this laboratory (see Svirbely & Pesce 1987). The assay as reported demonstrated replication of p = 0.96, sensitivity 0.05 mg/L, linearity from 2 to 100 mg/L (r = 0.99), and freedom from interferences. In a separate ex­periment, the partition coefficients of sulphame­thoxazole and trimethoprim between n-octanol and phosphate buffer (pH 7.52) were measured. n-Oc­tanol was chosen as the organic phase because it approximates the partition characteristics of hu-

319

man tissue. The pH of 7.52 approximated the pH of dialysate during 80% of an exchange.

Pharmacokinetic Modelling

Blood and dialysate concentrations from the first exchange were generally fitted to a l-compartment body model using the NONLIN84 pharmacokin­etic modelling program (Metzler & Weiner 1985), with first-order exchange between blood and dialy­sate (table I). The 12-,24- and 48-hour samples in the PO study were not used in this model, but the blood samples from that study including those taken at 12, 24 and 48 hours were used to calculate plasma elimination half-lives for sulphamethoxa­zole and trimethoprim and the apparent volumes of distribution of both drugs. Trimethoprim blood data alone from 3 patients in the PO study were better fitted by a 2-compartmental model if the 12-, 24- and 48-hour samples were included. How­ever, when both the blood and dialysate trimetho­prim data were modelled for the first exchange only, to determine plasma to peritoneal fluid and peri­toneal fluid to plasma transfer rate constants and clearances, the data were better fitted by the 1-compartment equations in table I. For sulphame­thoxazole, first-order appearance and disappear­ance of the acetylated metabolite and its elimina­tion were incorporated into the equations. Input was either into the blood by first-order absorption from the gut (oral study) or directly into the peri­toneal space at time zero (intraperitoneal study). First-order return from dialysate (oral study) and from plasma (intraperitoneal study) were included, allowing separation and calculation of plasma-peri­toneal and peritoneal-plasma clearances for both sulphamethoxazole and trimethoprim. By using only the unbound fraction of each drug in mo­delling, the study eliminated any effect of protein binding on measured clearances. A constant per­centage free fraction was used for unbound tri­methoprim (Patel & Welling 1980) but the un­bound fraction of sulphamethoxazole was measured because, according to Reidenberg et al. (1984), binding of basic drugs such as trimethoprim is un­altered by the acidosis found in renal disease, while

Peritoneal Barrier Pharmacokinetics

Table I. Sets of differential equations, parameters and con­stants used in modelling

Sulphamethoxazole data from oral study

DZ(l) = [kOl ' Z(2)· fu' ::~ - kl0' Z(l)

f ka ' D • e-kat ~ DZ(2) = - kOI • fu • Z(2) -km • Z(2) Vd

DZ(3) = km • Z(2)

Trlmethoprlm data from oral study

DZ(l) = rOl • Z(2)' fu' ::~ - kl0' Z(l)

[ ka ' D • e-kat ] DZ(2) = L Vd J -kOI • fu • Z(2)

Co-trlmoxazole data from Intraperitoneal study

DZ(l) = fOt • Z(2)fu • ::] - kl0' Z(l)

Vd DZ(2) = kl0' Z(l) •

Vp

Abbreviations: Z(l) = dialysate concentration; Z(2) = plasma

concentration; Z(3) = metabolite concentration; DZ(l) = the de­

rivative of the change in the dialysate level with time; DZ(2) = the derivative of the plasma level/dt; DZ(3) = the derivative

of the metabolite level with respect to time; fu = fraction un­bound in plasma; Vd = volume of distribution; Vp = volume of

peritoneal dialysate; km = apparent metabolism rate constant; kOl = plasma to peritoneal compartment transfer rate constant;

kl0 = peritoneal to plasma compartment transfer rate constant;

t = time/dose interval; D = dose; ka = absorption rate constant; ka • D • e-katjVd = absorbance from gut.

320

the binding of acidic drugs such as sulphamethox­azole is decreased compared with that in healthy individuals.

The following kinetic parameters were esti­mated: apparent volume of distribution (Vd), ap­parent metabolic rate constant of sulphamethoxa­zole (km), plasma-peritoneal transfer rate constant (kol) and peritoneal-plasma transfer rate constant (klO). From these parameters, clearances were cal­culated as Vd x kol for plasma-peritoneal clear­ance, and klO x 2L for peritoneal-plasma clear­ance, 2L being the approximate volume of the dialysate. Criteria used to select or eliminate sets of differential equations and arrive at the models described by the equations in table I included com­parison of correlation matrices of the estimates, ei­genvalues of (A transpose A) matrices and calcu­lations of the corrected sum of squares and sum of squared residuals, all generated by the NONLIN84 program as measures of the reliability of the mo­delling. Analysis of variance was performed on the clearance values, using the SAS statistical program (SAS 1985), to test for effect of direction (plasma­peritoneal versus peritoneal-plasma) and of drug (sulphamethoxazole versus trimethoprim).

Results

The partition coefficient of trimethoprim was 5.1 in the n-octanol buffer system. Sulphamethox­azole did not partition measurably into n-octanol. The mean protein binding of sulphamethoxazole was 54%, lower than the published figure of 66% (Patel & Welling 1980); percentage binding did not vary with concentration. Sample decay curves for I patient are shown in figure I; these are typical of the pharmacokinetic behaviour and concentra­tions found with the other 4 patients. It should be noted that the sulphamethoxazole metabolite, N­acetyl-sulphamethoxazole, did not transfer across the peritoneal barrier from the plasma to the di­alysate to a significant extent during the first ex­change.

Pharmacokinetic data pooled from the oral and intraperitoneal studies are given in table II. Rate constants and clearances were first calculated sep-

Peritoneal Barrier Pharmacokinetics

30

10

a

5,0

i

i .9 0,5

e

o 2 3 4 5 6

,. .. __ .. -_ .................................... _-.. _---_ .. _--...... ..

o

( I i

2

Time (hI

3 4 5 6

321

100

10

b o 2 3 4 5 6

10,0

1,0

o 2 3 4 5 6

d Time (hI

Fig. 1. Drug concentration data over the first exchange for 1 patient in both oral [(sl sulphamethoxazole; (el trimethopriml and

intraperitoneal [(bl sulphamethoxazole; (dl trimethopriml studies; (-I = plasma drug concentration; (--I = dialysate drug concen­tration; (00,1 = plasma N-acetylsulphamethoxazole concentration,

Peritoneal Barrier Pharmacokinetics 322

Teble II. Pharmacokinetic data (± ASeS ) pooled from oral and intraperitoneal studies. Plasma-peritoneal clearance was consistently

greater than peritoneal-plasma clearance (p < 0.01). Clearance of trimethoprim was significantly greater than that of sulphamethox­

azole in both directions (p < 0.0001)

Parameter (drug) Patient no.

[units) 2 3 4 5

Weight [kg) 61.3 84.2 86.2 61.4 141 Surface area [m2J 1.74 1.95 2.02 1.72 2.71 Percentage protein binding (SMZ) 47 69 54 61 37 km (SMZ) [h-1) 0.182 0.167 0.141 0.125 0.113

(± 0.026) (± 0.029) (± 0.053) (± 0.013) (± 0.042) Vd (SMZ) [L) 14.6 17.4 8.2 19.5 35.4

(± 1.8) (± 2.1) (± 37.5) (± 1.1) (± 10.2) Vd (TMP) [L) 22.4 122 44.3 130 193

(± 909) (± 12.6) (± 36.3) (± 4.9) (± 52.5) kOl (SMZ) [h-1) 0.067 0.120 0.127 0.045 0.030

(± 0.028) (± 0.064) (± 0.679) (± 0.011) (± 0.023) kOl (TMP) [h-1) 0.049 0.020 0.040 0.202 0.005

(± 1.97) (± 0.008) (± 0.063) (± 0.010) (± 0.004) kl0 (SMZ) [h-1) 0.066 0.52 0.197 0.199 0.372

(± 0.146) (± 0.45) (± 0.038) (± 0.109) (± 0.469) kl0 (TMP) [h-1) 0.198 0.569 0.684 0.959 0.423

(± 0.098) (± 0.392) (± 1.04) (± 0.247) (± 0.029) Plasma-peritoneal clearance (SMZ) [ml/h)b 1000 2100 1040 882 1060

(± 340) (± 986) (± 1330) (± 216) (± 686) Plasma-peritoneal clearance (TMP) [ml/h)b 1090 2420 1750 2620 884

(±210) (±949) (± 1830) (± 1330) (±722) Peritoneal-plasma clearance (SMZ) [ml/h)C 133 1040 393 398 744

(±291) (±899) (±76.6) (±217) (± 895) Peritoneal-plasma clearance (TMP) [ml/h)C 397 1140 1370 1920 847

(±197) (±784) (±2090) (± 494) (± 58.5)

a Asymptotic standard error calculated by NONLlN84 program (Metzler & Weiner 1984) for each parameter; not the standard

deviation of the mean.

b Calculated as Vd x kOl.

c Calculated as k10 x Vp. Abbreviations: SMZ = sulphamethoxazole; TMP = trimethoprim; Vd = volume of distribution; k01 = rate constant for plasma-peritoneal transfer; k10 = rate constant for peritoneal-plasma transfer; km = apparent rate constant for metabolism of sulphamethoxazole to

N-acetylsulphamethoxazole; Vp = approximate volume of dialysate (2L).

arately for each study, and were combined for each of the 3 patients who participated in both studies, after analysis of variance had established that route of administration did not affect either rate con­stants or clearances. The reliability of the kOI and k 1 0 transfer rate constants in table II as measured by a number of indicators was independent of the route of administration and acceptab)e for non-lin­ear modelling. The results in table II show that plasma-peritoneal clearance was consistently greater than peritoneal-plasma clearance (p < 0.01), re­gardless of route of administration. Clearance of

trimethoprim was found to be significantly higher than that of sulphamethoxazole in both directions across the peritoneal barrier (p < 0.0001).

Discussio"

The rate of transfer across the peritoneal barrier should be inversely proportional to the square root of the molecular weight of the solute mass (De­drick et at. 1982; Sorkin & Nolph 1981). The ratio of the square roots of the molecular weights of tri­methoprim and sulphamethoxazole is 17: 16, so

Peritoneal Barrier Pharmacokinetics

close to unity that difference in molecular weight cannot explain the differences in clearance between the 2 drugs.

Protein binding restricts the amount of drug available for transfer, since only unbound drug passes freely across the peritoneal barrier. Tri­methoprim is about 45% bound to plasma proteins (Patel & Welling 1980). Mean binding (± SD) of sulphamethoxazole to plasma proteins in the 5 patients in the current study was 54 ± 12% (table I). Any effect of plasma protein binding was elim­inated in the study by modelling the movement of free rather than total drug. There is a lack of in­formation on tissue binding and intrinsic distri­bution characteristic for co-trimoxazole (Patel & Welling 1980), but tissue binding in the central compartment, although it may affect the apparent volume of distribution, would not affect transper­itoneal transfer of the drugs.

Polar molecules, with low lipid solubility, are hindered in their passage across lipoid barriers un­less they are very small. Sulphamethoxazole is suf­ficiently polar that it did not partition measurably into the organic phase of the n-octanol/phosphate buffer system. Trimethoprim, however, has a par­tition coefficient of 5.1 in this system, representing fairly high lipid solubility for an orally admini­stered drug. Thus, the greater clearance of tri­methoprim, in both directions across the periton­eal barrier, is consistent with the relative polarities of the 2 drugs.

Degree of ionisation affects transfer in a way similar to polarity: the un-ionised form of the mo­lecule is favoured over the ionised form as they move through the peritoneal barrier, because the latter interacts with charged groups within the bar­rier. Furthermore, because equilibrium across a li­poid barrier is established for un-ionised drug, the degree of ionisation of the drug in solution on either side of the barrier should control the transbarrier ratio of total drug concentrations at equilibrium.

The pKa of sulphamethoxazole, an acidic drug, is 5.7; that of trimethoprim, a basic drug, is 6.6. The Henderson-Hasselbach equation can be used to calculate the effect of pH on the degree of ion­isation of co-trimoxazole in dialysate and in blood.

323

The pH of dialysate in CAPD is 7.5 for 5 of the 6 hours of a typical exchange (Robson et al. 1981); at that level sulphamethoxazole would be 98.4% ionised and trimethoprim 11.2%. In blood also, sulphamethoxazole should be much more highly ionised than trimethoprim. At the typical blood pH of a CAPD patient (Teehan et al. 1981) of 7.35, sulphamethoxazole would be 97.8% ionised and trimethoprim must also contribute to its greater clearance in both directions across the peritoneal barrier.

Similar observations concerning the importance of polarity and degree of ionisation as determin­ants of peritoneal transfer rate in the rat were made by Torres et al. (1978). These investigators studied uptake from the peritoneum into the systemic cir­culation of compounds with varying partition coef­ficients, molecular weights and degrees of ionisa­tion. In order to maximise the surface area of the peritoneum, they measured absorption from large volumes of fluid (50 ml) in female Sprague-Dawley rats weighing 200 ± 50g, utilising a dwell time of I hour. Uptake was strikingly dependent on both partition coefficient and molecular weight. Ab­sorption ofa series of barbiturates ranged from 96% for thiopentone, with a partition coefficient of 3.3, to 57% for barbitone with a partition coefficient of 0.001. The degree of ionisation also affected up­take. Absorption of a series of acidic compounds ranged from 76% for salicylate, almost completely ionised at physiological pH, to 95% for phenol, largely un-ionised. In the case of basic compounds, caffeine, mostly un-ionised, was 68% absorbed while atropine, mostly ionised at physiological pH, was 27% absorbed.

In the current study, the basic compound tri­methoprim (89% un-ionised at pH 7.5) was 57% absorbed from the human peritoneum during the first hour of dialysate dwell time, while the acid sulphamethoxazole (only 1.6% un-ionised at dialy­sate pH) was only 27% absorbed during the first hour. These values are somewhat lower than those recorded by Torres et al. (1978). Apart from the species difference, the direction of net fluid flux in the 2 studies was different. Because an osmotically active compound was not included in the perito-

Peritoneal Barrier Pharmacokinetics

neal instillate in the Torres et al. study, fluid flux favoured absorption; these authors measured an uptake of 10.5% of the 50ml instillate during the first hour. In the present study, net fluid flux was in the direction of transfer from plasma to peri­toneum because the dialysate was osmotically ac­tive due to the addition of 1.5% dextrose. Pyle et al. (1981) estimated the net movement of fluid to be about 300ml in the course of a 4 to 6 hour ex­change. This fluid flux constitutes a pressure which may overcome some of the resistance to transfer from plasma to peritoneum, but which itself con­stitutes a resistance to be overcome during peri­toneal-plasma transfer. The result is that transfer in the direction of net fluid flux is favoured over transfer in the opposite direction. Thus, the net fluid flux from plasma to peritoneum in the current study is a reasonable explanation for the observation that plasma clearances were larger than peritoneal clearances. However, the net fluid flux, although demonstrating a mean of 300ml over 6 hours with a 1.5% dextrose dialysate, also demonstrates con­siderable variability (Pyle et al. 1981) which may account for some of the intrapatient variation in the clearances found in this study.

It should be emphasised that these clearances, calculated for transfer from plasma to peritoneum and from peritoneum to plasma, are not compar­able to the net clearances calculated in studies in which the approach-to-equilibrium nature of CAPD was not taken into account. Net clearances, cal­culated using the formula:

Clearance = D/AUC

where D is the amount of drug absorbed or re­covered from dialysate and AUC (area under the concentration/time curve) is determined directly from the plasma or serum concentration/time graph, are sensitive to dwell time; that is, to the extent to which return from peritoneum to plasma has influenced the AUC. At the beginning of an exchange the concentration gradient across the bar­rier favours plasma-peritoneal transfer in oral administration studies but at the end of an ex­change the gradient equalises, aided by the flux of water into the dialysate.

324

While the approach used in the present study, and in others, is a grouped-parameter one in which a series of differential equations define transfer, Flessner et al. (1982) and Dedrick et al. (1984) have used physiological measurements such as pore ra­dius and pore density to estimate capillary level solute permeability, and measurements and esti­mates for void fraction, retardation factor, tissue tortuosity, and tissue diffilsivity to determine transport in the peritoneal barrier tissue space. This distributed model allows a thorough grasp of transfer phenomena, especially within the perito­neal barrier tissue, and is valuable for predicting methods of manipulating various parameters to respond to the demands of experimental or clinical conditions. However, the grouped-parameter approach used in the present study is capable of predicting plasma and peritoneal fluid con­centrations more easily than the distributed model.

Based on the plasma data alone from the oral study, the apparent half-life of sulphametholazole ranged from 4.5 to 28.9 hours, which is similar to the range of elimination half-lives found in healthy individuals (Patel & Welling 1980). The mean metabolic rate constant for sulphamethoxazole (table II) was 0.15 ± 0.03 h-1, which corresponds to a half-life of metabolism of 4.5 hours. Thus, a large fraction of sulphamethoxazole elimination from the plasma is due to metabolism. Less than 10% of trimethoprim is metabolised (Patel & Well­ing 1980), and its half-life was 30.2 to 74.7 hours in patients in this study, substantially greater than in renally sufficent persons in whom the mean elimination half-life is approximately 12 hours (Pa­tel & Welling 1980). The extent to which sulpha­methoxazole is metabolised is the determining fac­tor in its shorter half-life compared with trimethoprim.

The results demonstrate that transfer across the peritoneal barrier is similar in behaviour to trans­fer across many other barriers. This observation is consistent with the relative lipid solubilities and degrees of ionisation of sulphamethoxazole and tri­methoprim.

Peritoneal Barrier Pharmacokinetics

Therapeutic I mpliclltions

The clinical implication of these findings is that co-trimethoxazole can be used effectively to treat sensitive intraperitoneal and systemic infections in CAPD patients. This finding agrees with those of other published studies (Halstenson et al. 1984; Singlas et aI. 1981).

Our clinical experience in treating peritoneal in­fections with co-trimethoxazole is that the best strategy is to use both oral and intraperitoneal administration in order to obtain effective sulpha­methoxazole concentrations in the peritoneum.

Acknowledgements

We would like to thank Dr S.A. Myre, Dr P.D. Ham­mond, Dr E. Foulkes, and F.M. Hassan for helpful dis­cussion. We would also like to thank Bettye Morgan, R.N., and Audrey Dale, R.N., for helping with the clinical por­tions of the study.

Research was supported by grants from the Endow­ment Fund of the American Association for Oinical Chemistry and from the Kidney Foundation of Greater Cincinnati.

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Authors' address: Joseph E. Svirbely. Ohio River Division la­boratory. US Army Corps of Engineers, 5851 Mariemont Avenue.

Cincinnati. OH 45227-0618 (USA).