Pivampicillin and ampicillin in bile, portal and peripheral blood In 7 patients with a catheter in the portal vein and a T tube in the common bile duct, the concentration of unhydrolyzed pivampicillin and of ampicillin was measured simultaneously in portal and peripheral blood and in bile after oral administration of 700 mg pivampicillin. In both portal and peripheral circulation the concentration of unhydrolyzed pivampicillin was always less than I % of the levels of ampicillin, indicating the effectiveness of the intestinal mucosa in the hydrolysis of pivampicillin. Evidence for the ability of the liver to excrete ampicillin against a concentration gradient into the bile was established by direct measurements. Only about I % of the dose given could be recovered in the bile. There was an unexplained reduction of about 70% in the absorption of the drug induced by the catheter itself.

Birger Lund, M.D., Jens P. Kampmann, M.D., Finn Lindahl, M.D., and Jens Molholm Hansen, M.D. Copenhagen, Denmark Medical Department F and Surgical Department S, Gentofte Hospital

Pivampicillin, a pivaloxymethyl ester of ampicillin, is rapidly hydrolyzed to ampicillin in vitro by enzymes from serum, the gastrointestinal mucosa, and other tissues. 1 In man, the concentration of nonhydrolyzed pivampicillin in peripheral blood is less than 1% of the concentration of ampicillin, suggesting that the pivampicillin-ester is hydrolyzed to a great extent during the phase of absorption-but the hydrolysis could also take place in the liver, since it has been shown that liver homogenates have a great capacity for hydrolyzing pivampicillin. 2 In an earlier investigation we examined the nature of the transport of ampicillin from blood to bile. 6 By comparing the concentration of ampicillin in portal blood in one group of patients with the concentration of ampicillin in Received for publication Oct. 23. 1975. Accepted for publication Nov. 7. 1975. Reprint requests to: Dr. Birger Lund. Medical Department E, Frederiksberg Hospital. Copenhagen, Denmark.

bile in another group of patients it was found that the peak concentration of ampicillin after an oral dose of pi vampicillin was twice as high in portal blood and in bile as the levels in peripheral blood. This might indicate a passive transfer of ampicillin from portal blood to bile. The problem of the nature of the transport can be examined more directly in patients with catheters in the portal vein and in the common bile duct. The purpose of our investigation was to measure unhydrolyzed pivampicillin in portal blood and bile and by simultaneous determinations of ampicillin concentrations in portal and peripheral blood and in bile to deduce the influence of the liver on the excretion of ampicillin. Materials and methods

Seven patients, aged 50 to 83 yr, were examined 7 to 10 days after an uncomplicated cholecystectomy. Weight varied from 53 to 78 kg. During the operation a baby-feeding tube 587

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14

AMPICILLIN CONG. microg/ml AUC

• BILE A PORTAL BLOOD

12

microgxh/ml 19.0

o PERIPHERAL BLOOD

13.0

10 B

6 4 2

2

3

4

5

6

7

B

9 HOURS

Fig. 1. Mean concentrations of ampicillin in bile, portal and peripheral blood after oral administration of 700 mg pivampicillin (equivalent to 500 mg ampicillin) to 7 patients. The mean area under the peripheral curve has been calculated to be 13.3 J,tg/ml x hr. was inserted into the portal vein through the obliterated umbilical vein with the purpose of collecting portal blood. The catheter was postoperatively kept open by constant infusion of heparinized saline. Bile was collected from a T tube in the common bile duct. At the time of the investigation all of the patients were mobile and had normal bowel habits and, as indicated by serum concentrations of bilirubin, alkaline, phosphatase, and creatinine normal hepatic and renal function. Pivampicillin (Pondocillin), 700 mg (equivalent to 500 mg ampicillin), was given by mouth and the concentration of pi vampicillin in portal and peripheral blood was followed by frequent blood sampling the next 2 hr. The concentration of ampicillin in the bile and in peripheral and portal blood was followed for 10 hr at intervals shown on the figures. Eight additional patients served as a control group with the purpose of investigating the influence of the catheter itself on the process of absorption. These patients were comparable with respect to age, weight, hepatic and renal function to the patients with the portal catheter. The patients were studied 5 to 7 days after cholecystectomy and had only a T tube in the com. mon bile duct. After oral administration of 700

mg pivampicillin, the concentration of ampicillin was followed in peripheral blood. The concentration of pivampicillin in serum was determined by the agar cup method after extraction of 1.5 ml heparinized full blood with a mixture of 1 ml icecold citric buffer (0.15 M) and 4 ml ether. The mixture was shaken vigorously and the organic layer was separated and washed with 1 ml citric buffer (0.15 M, pH 7.2). The ether extract containing unhydrolyzed pivampicillin was filtered and evaporated to dryness and subsequently dissolved in 200 ILl citric buffer containing 1% mouse serum (addition of mouse serum 1% hydrolyzes pivampicillin to ampicillin). Ampicillin concentrations were measured by the agar diffusion method with Sarcina lutea Leo strain [CO (F)], a variant of strain ATCC 9341, as test organism and ampicillin as reference compound. Test medium was agar medium NIH (Difco). * Since the patients were recently operated on, and a wide variation in the time lapse from the moment of application to the arrival of the drug at the site of absorption could be expected, we have used a nonparametric pharmacokinetic

*These analyses were carried out at the Microbiological Laboratory of Leo Pharmaceutical Products.

Absorption and hydrolysis of pivampicillin

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AUC

AMPICILLIN CONC.

microg/ml

17.5

I

I

12.5

o

I

10.0 7.5

5.0

microg ,h/ml

(\

15.0-

o

r

45.6

0

\ 0

\

0\ 0\ ~o

0

2.5-

589

~o

1

o

----0---0__0

-0

3

4

5

8

6

10 HOURS

9

Fig. 2. Mean ampicillin concentration in peripheral blood in 8 patients with a T tube in the common bile duct after 700 mg pivampicillin orally. The mean area under the curve has been calculated to be 45.6 fLg/ml x hr.

model developed by Engberg-Pedersen. 3 This model accounts for the individual variation in the lag time of the absorption of the drug after oral administration.

PIVAMPICILlIN CONC.

microg/ml

o

PERIPHERAL BLOOO

A PORTAL BLooO

Results

Fig. 1 shows the mean ampicillin concentration from the 7 patients in bile and in portal and peripheral blood. The highest concentration was found in the bile with a maximum of 11.8 ILg/ml after 2.4 hr. A maximum of7.3 ILg/ml was reached at 1.7 hr in the portal blood at the same time as the maximal concentration in peripheral blood (4.5 ILg/ml), namely, 1.7 hr. Five hours after the administration of pivampicillin the concentrations in portal and peripheral blood were identical, indicating termination of the absorption. In spite of the high concentration in the bile, the total amount of ampicillin excreted by this route was only about 1% of the dose. Fig. 2 shows the ampicillin concentration in peripheral blood in the 8 patients without the portal catheter after 700 mg pivampicillin. In contrast to those with the portal catheter, these patients had more rapid and more complete absorption. The maximal concentrations were achieved at 1.2 hr with a value of 17.2 ILg/ml, indicating that the portal catheter delayed absorption. The concentration of unhydrolyzed pivampi-

001

15

30

45

60

75

90

120 MINUTES

Fig. 3. The concentration of unhydrolyzed pivampicillin in portal and peripheral blood after administration of 700 mg pivampicillin orally to 7 patients. The vertical bars indicate ± SD.

cillin in portal and peripheral blood is shown in Fig. 3. The concentration of pivampicillin in portal blood does not correlate with the concentration of ampicillin and is constant during absorption at a level of about 0.03 ILg/ml. A similar pattern but at a lower concentration was found in peripheral blood (0.01 ILg/ml). These concentrations represent less than 1% of the corresponding values of the ampicillin concentrations. No unhydrolyzed pivampicillin could be demonstrated in the bile.

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Table I Patient

1 2 3 4 5 6 7

I

Mean

A UC (/Lg x hr/ml) peripheral blood

AUC (/Lg x hr/ml) portal blood

Absorbed drug (mg)

Portal flow (mllmin)

20.55 13.55 10.37 8.13 10.49 11.21 18.45

22.68 14.42 11.11 13.45 14.38 24.79 26.45

225 149 114 89 115 123 202

1,761 2,845 2,561 279 493 151 421

13.3

18.2

145

1,210

absorbed ampicillin Calculations of portal blood flow: AUC (portal) _ AUC (peripheral); 100% absorption

=

500 mg

=

45.6 /kg X hr/ml (mean value from 8

. . AUC (peripheral) patIents wIthout portal catheter); absorbed ampicillin: 45.6 x 500 mg.

An estimate of the portal blood flow may be calculated from these curves using Fick principle by dividing the absorbed amount of drug with the average difference in serum concentrations in portal and peripheral blood. Absorbed ampicillin in the patients with a portal catheter is estimated from the relationship between areas under the curves in peripheral blood in patients with and without portal catheter, assuming complete absorption in the latter group. The difference in concentrations in portal and peripheral blood during absorption represents the amount of drug added to portal blood from the gut. Therefore, the average difference in area under the curves in portal and peripheral blood represents the average difference in serum concentrations in portal and peripheral blood. Using the values from the 7 patients studied, a mean portal blood flow of 1.2 L/min (Table I) was calculated. Discussion

Our study confirms a previous investigation in showing that only insignificant amounts of orally administered pivampicillin reach the general circulation. 2 Our measurements of pivampicillin concentrations in portal blood during the phase of absorption have shown that the hydrolysis of pivampicillin occurs mainly in intestinal tissue. The higher concentrations of pivampicillin in portal compared to peripheral blood might partly be due to a con-

centrating effect, as the drug is primarily mixed with the relative small blood volume of the splanchnic area, and partly to hydrolysis in the liver. The concentration of pivampicillin in portal and peripheral blood was always less than 1% of the corresponding values of ampicillin, indicating the effectiveness of the in vivo hydrolysis of ampicillin. No unhydrolyzed pivampicillin could at any time be found in the bile. By studying the ampicillin concentrations in patients with both a catheter in the portal vein and a T tube in the common bile duct, direct proof has been obtained of the ability of the liver to excrete ampicillin into the bile against a concentration gradient. This result is at odds with our previous report, but we had not had the opportunity of studying patients with catheters simultaneously in the portal vein and in the common bile duct. The concentration of ampicillin in peripheral blood of the patients with a portal catheter was lower than found by others and ourselves in previous studies 1, 4, 5, 6 of patients without portal sampling. This could be due to a reduction of the amount of absorbed drug caused by the portal catheter itself. By comparing the areas under the peripheral ampicillin concentration curves from the patients with both a catheter in the portal vein and a T tube in the common bile duct to the patients with only a biliary T tube, a decrease in the absorbed dose of about 70% was indicated (13.3 and 45.6 JLg

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x hr/ml). A similar reduction in absorption caused by a portal catheter has been found in the case of propylthiouracil. * The nature of the influence of the portal catheter is not clear. It has been found that the absorption of glucose is unaffected by a catheter in the portal vein. 7 It may be that only the passive transport of drugs is inhibited. A reduction of the intestinal blood flow cannot be the sole explanation, since not only the absorption rate but also the absorbed fraction is reduced. The results may be of importance in studies of drug concentrations in portal blood. Simultaneously, measurements in peripheral and portal blood make it possible to estimate absorption of drugs from the intestine since the difference in concentrations is due to absorbed drug, previous studies having shown identical concentrations after intravenous administration. 6 On this basis we found values from 300 to 2,800 ml in portal flow, which are in accordance with other reports.8 More accurate estimations can be obtained by measurements of the distribution volume and the amount of drug absorbed. * Kamprnann,

J.: Personal communication.

References 1. Daehne, W. von, Frederiksen, E., Gundersen, E., Lund, F., M~rch, P., Petersen, H. 1., Roholt,

Absorption and hydrolysis of pivampicillin

2.

3.

4.

5.

6.

7.

8.

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K., Tybring, L., and Godtfredsen, W. 0.: Acyloxymethyl ester of ampicillin, J. Med. Chem. 13:607-612, 1970. Daehne, W. von, Godtfredsen, W. 0., Roholt, K., and Tybring, L.: Pivampicillin, a new orally active ampicillin ester, Antimicrob. Agents Chemother. 10:431-437, 1970. Engberg-Pedersen, H.: An empirical equation for pharmacokinetic analysis of drug serum levels after oral application, Antimicrob. Agents Chemother. 6:554-562, 1974. Foltz, E. L., West, 1. W., Breslow, I. H., and Wallick, H.: Clinical pharmacology of pivampicillin, Antimicrob. Agents Chemother. 10:442454, 1970. Loo, 1. C. K., Foltz, E. L., Wallick, H., and Kwan, K. C.: Pharmacokinetics of pivampicillin and ampicillin in man, CUN. PHARMACOL. THER. 16:35-43, 1974. Lund, B., Mogensen, C., M~lholm Hansen, J., Kampmann, J., and Siersbxk-Nielsen, K.: Ampicillin in portal and peripheral blood and bile after oral administration of ampicillin and pivampicillin, Eur. J. Clin. Pharmacol. 7:133-135,1974. Lund, B., Schmidt, A., and Deckert, T.: Portal and cubital serum insulin during oral, portal and cubital glucose tolerance tests, Acta Med. Scand. 197:275-281, 1975. Strandell, T., Erwald, R., Kulling, K. G., Lundbergh, P., Marions, 0., and Wiechel, K. L.: Simultaneous determination of portal vein and hepatic artery blood flow by indicator dilution technique in awake man, Acta Med. Scand. 191: 139-140, 1972.

Pivampicillin and ampicillin in bile, portal and peripheral blood.

In 7 patients with a catheter in the portal vein and a T tube in the common bile duct, the concentration of unhydrolyzed pivampicillin and of ampicill...
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