Br. J. clin. Pharmac. (1979), 8, 491-495

PROBENECID: AN UNEXPLAINED EFFECT ON CEPHALOSPORIN PHARMACOLOGY P.G. WELLING*, S. DEAN, A. SELEN*, M.J. KENDALL & R. WISE Department of Therapeutics and Clinical Pharmacology, The Medical School, Birmingham, and the Department of Medical Microbiology, Dudley Road Hospital, Birmingham

1 The influence of probenecid on serum levels and urinary excretion of orally administered cephradine and cefaclor has been investigated. 2 Probenecid caused serum levels of both antibiotics to be increased and also prolonged. Urinary excretion of antibiotic activity was slightly but not significantly decreased by probenecid during the initial 6 h postdosing. It was significantly increased in 6-12 h urine, but only a small percentage of the doses were excreted during that period. 3 The increased serum levels of antibiotic were greater than could be accounted for by reduced elimination rate alone. Possible mechanisms to account for increased circulating levels of antibiotic in the presence of probenecid are discussed in the light of previous observations on probenecid induced changes in tissue distribution of fi-lactam antibiotics.

Introduction

Methods

The ability of the uricosuric agent probenecid to inhibit renal tubular secretion and to cause increased and prolonged circulating levels of penicillin and cephalosporin antibiotics is well documented (Klein & Finland, 1963; Griffith, Black, Brier & Wolny, 1977; Bint, Reeves and Holt, 1977). While the prolongation of drug levels in the body is thought to be related to competitive inhibition for renal active transport processes, the mechanism causing increased circulating levels in the presence of probenecid is less clear. In an analysis of earlier data, Gibaldi & Schwartz (1968) suggested that delayed elimination could not account for the extent to which circulating levels of penicillins and a cephalosporin were increased by probenecid, and proposed that a reduction in drug distribution volume had occurred. In a subsequent study using two-compartment model kinetics, Gibaldi, Davidson, Plant & Schwartz (1970) concluded that apparent reduction in distribution volume of intravenous benzylpenicillin due to probenecid was due to changes in the relative amount of drug in the central and peripheral compartments, in favour of the central compartment. We had an opportunity to examine the influence of probenecid on the pharmacokinetics of two oral cephalosporins in healthy individuals, and report here the results of these studies.

Subjects

*Present address: School of Pharmacy, University of Wisconsin, Madison, Wisconsin 53706, USA 0306-5251/79/080491-05 $01.00

Subjects were five healthy males (61-80 kg, 19-45 years) and five healthy females (55-70 kg, 18-34 years). All subjects underwent a clinical examination and gave informed consent to participate. Six individuals (three male) received single oral doses of 500 mg cephradine capsules (250 mg, E.R. Squibb and Sons Ltd, Twickenham, Middlesex) while six individuals (three male) received single oral doses of 500mg cefaclor capsules (250 mg, Dista Products Ltd, Basingstoke, Hampshire) on another occasion. Two subjects were common to both studies. Subjects were instructed to take no other drugs for 1 week before or during each study.

Protocols Cephalosporins were administered as two 250 mg capsules together with 100 ml water following overnight fast. Food and water were withheld until 4 h postdosing. Each cephalosporin was given alone and also in the presence of probenecid. In the latter case 500 mg probenecid (Benemid (500 mg) tablets, Merck Sharp and Dohme Ltd, Hoddesdon, Herts) was given orally at 08.00 h and 20.00 h on the day preceding the study, and at 07.00 h on the study day. Cephalosporins were administered at 09.00 h. Treatments with and without probenecid were © Macmillan Journals Ltd.

P.G. WELLING, S. DEAN, A. SELEN, M.J. KENDALL & R. WISE

492

randomized. One 7 ml blood sample was drawn from a forearm vein into glass tubes containing no anticoagulant immediatey before and ten further samples serially following each cephalosporin dose. Urine collections were obtained immediately before and then quantitatively during 0-6 and 6-12 h postdosing. Subjects sat up in bed during the first 6 h following cephalosporin doses, but were ambulatory after that time. Because of the chemical instability of cefaclor (Foglesong, Lamb & Dietz, 1978), all sera were separated from blood quickly by centrifugation and immediately frozen. Urines were frozen at the end of each collection interval. All dosing and sampling procedures were carried out in a side room at the Queen Elizabeth Hospital, Birmingham. Sera and urine samples were transported frozen for assay to the Medical Microbiology Department, Dudley Road Hospital, Birmingham. Assays were done within 48 h of sampling. Assay

Cephalosporin concentrations were determined by a plate diffusion method using Penassay No. 1 antibiotic agar (Oxoid) as growth medium and B. subtilis ATCC 6633 as test organism. The 95% confidence limits of the assay were routinely less than ±16%. Data analysis

Serum cephalosporin profiles were analyzed in term,s of simple one-compartment kinetics (Wagner, 1975). With this model drug concentrations C in serum are described by Equation 1, where F is the fraction

C = FD

[ka

][ e - kel (t-to)-e - ka (tto)]

(Equation 1) of dose D absorbed, V is the apparent body distribution volume for the drug, ka and kei are firstorder rate constants for drug appearance and elimination from serum respectively, t is the total time elapsed after dosing and to is the apparent lag time between dosing and the start of drug adsorption. Data obtained in the presence and absence of probenecid were compared by paired t-test.

Results

Serum concentrations and urinary excretion details for both cephalosporins are given in Tables 1 and 2. Serum data are summarized in Figure 1. From Table 1 it is clear that, apart from the period within one hour of dosing, probenecid caused a significant increase in serum levels of both cephalosporins. During 1-2 h postdosing probenecid caused at least a two-fold increase in antibiotic levels. The influence of probenecid increased further at later times and the duration of detectable levels of both cephalosporins

prolonged. Probenecid tended to reduce the concentration of cephalosporins and also the percentage of dose cleared in 0-6 h urine, but the reduction was not statistically significant. Total urinary recovery of both antibiotics was significantly increased during the 6-12 h collection interval, but only a small percentage of the doses were excreted during this period. The data in Table 3 demonstrate the similar effect of was

Table 1 Serum levels (mean+ s.d.) of cephalosporins following single 500 mg oral doses Time

(h) 0

0.25 0.5 1

1.5 2 3 4 5 6 8

Serum cephradine (pg ml-')

+probenecid' 0

0.7i1.7

6.3+ 5.9 22.1 +4.6 24.4± 6.6 12.1 +3.8 8.2+ 2.1

4.9i1.7

-probenecid'

+probenecid' 0

0

NS2

0.4+0.6 8.4+7.1

2.1 +1.6

0

0.1 +0.3 7.6 5.2 12.4+ 5.8 10.7+3.2

6.8 1.9 2.7 + 1.9 1.3 + 0.7

3.1 +1.6 1.8+ 1.2

0.5+0.5 0.1 ±0.3

0.7±0.6

0

ml-') -probenecid'

Serum cefaclor (pg P

NS < 0.02 < 0.02 < 0.02

Probenecid: an unexplained effect on cephalosporin pharmacology.

Br. J. clin. Pharmac. (1979), 8, 491-495 PROBENECID: AN UNEXPLAINED EFFECT ON CEPHALOSPORIN PHARMACOLOGY P.G. WELLING*, S. DEAN, A. SELEN*, M.J. KEND...
568KB Sizes 0 Downloads 0 Views