Biomaterials, Artificial Cells and Immobilization Biotechnology

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Acute Effects of Moderate Fluosol-DA Hemodilution on Hepatic Microsomal and Nonmicrosomal Metabolism in Rats Robert P. Shrewsbury To cite this article: Robert P. Shrewsbury (1992) Acute Effects of Moderate FluosolDA Hemodilution on Hepatic Microsomal and Nonmicrosomal Metabolism in Rats, Biomaterials, Artificial Cells and Immobilization Biotechnology, 20:2-4, 1037-1043, DOI: 10.3109/10731199209119760 To link to this article: http://dx.doi.org/10.3109/10731199209119760

Published online: 11 Jul 2009.

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BIOMAT., ART. CELLS & IMMOB. BIOTECH., 2 0 ( 2 - 4 ) , 1037-1043 (1992)

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ACIJ’I‘E EFFECTS OF M0I)I’KAI‘E 1LIJOSOL-DA HEMUDILUTION ON HEPATIC MICROSOMAL AND NONMICKOSOMAI. MEIABOLISM IN RATS Robert 1’. Shrewstwry Division of Pharmaceutics, School of Pharmacy University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 A13SI’KA. IN’~R0DlJ~I‘ION

The hepatic uptake of perfluorochernical (PFC’) emulsion particles was discovered early in the development o f these blood SubStiluteS. Therefore, it was not surprisin that 5tudies in rats dcrnonstrated that the disposition of several drugs was altered immeiately after PIX’ emulsion administration. Studies included testosterone (1,2), diazepani (3,4), antipyrine (3). aspirin ( 5 ) , morphine (6), penicillin (3.4.7). phenytoin (X,Y), sulfamethazinc (3). indocyanine green ( 10.1 1 ). and bromsulfophth;ileiri (10). The initi:tl work in our laboratory was to determine if PFC ynulsion administration affected the disposition of drugs in a time dependent manner. I’hese studies included ampicillin (12). antipyrine ( I3,14), indocyanine green (15). prolmnolol (15). phenytoin (Ih), and warfarin ( 17). The studies with antipyrine, phenytoin, and warfarin showed i l i : i t microsomal cytochrome P-450 activity was influence(; in a time dependent manner but t1i;ht the influence involved selected isoenlymes and was not a universal effect. The indocyanine green ;ind propranolol s!udies showed that hepatic Iilood flow. a major factor in hepatic nietaholism, was not significantly altered in a time deperidcnt manner. The lack of influence on hepatic blood flow was coniirmed using an alternate methodology (18). The work in o u r I;ibor;itory also showed that cytochrorne P-450 activity was altered in a PFC (lose dependent manner (14,lh.lY). The first of these studies was presented at the 3rd International Symposium o n Blood Substitutes (20). One atltlitional study from our

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laboratory reported that the phenobarbital inducible cytochrome P-450 isoenzyme activity was liiore dramatically increased in male rats than in female r;its (21).

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One other investi ation originally presented at the 3rd International Symposium showed that cytochrome f-450 content was increased b 3 days and remained elevated for 200 days after a single injection of Fluosol-DA (22J3). Additional studies appearing between 1985-1989 indicated that perfluorodecalin and perfluorotriprop lamine either singly or in combination induce the phenobarbital inducible cytochrome P-4& isoenzymes within 72 hours, and produce an unprecedented prolongation of hepatic microsomal induction (2430). The initial phase of our research determined the time dependent nature of microsomal cytochrome P-450 activity after a single Fluosol administration. As mentioned above, the induction of cytochrome P-450 activity is ve protracted, and the long term effects on drug disposition warrant further investigation. %owever, we have expanded our original focus to investigate the time dependent effect of PFC emulsions on such nonmicrosomal pathw? as sulfation, acetylation, and glucuronidation. To date, the acute effect of Fluosol hemo ilution on the phenobarbital inducible microsomal tochrome P-450 isoenzyme activity and the nonmicrosomal pathways of sulfation and acetyration have been completed. These results are the subject of this report. MATERIALS AND METHODS The disposition of 3 drug markers, antip rine, acetaminophen (APAP), and sulfamethazine (SMZ) was determined in rats after bluosol hemodilution. Male, Sprague Dawley rats were hemodiluted with 40 ml/kg of Fluosol using a procedure developed in our laboratory which reduces the hematocrit approximately 50% with a 5% fluorocrit (31). At 0.5, 24, 48 and 72 hours after hemodilution, the drug markers were intravenously administered to separate groups of animals, and the disposition of the parent and its metabolite(s) was determined. The harmacokinetic parameter used to quantitate in vivo enzymatic activity was the metabolte’s formation clearance (CIF). 3-Hydroxymethyl antipyrine (3-OHME) CIF quantitates phenobarbital inducible (P-45Ob and P-450,) microsomal cytochrome P-450 isoenzyme activity, while the CIF of acetaminophen sulfate (APAP-S) and acetylsulfamethazine (ASMZ) quantitates nonmicrosomal sulfation and acetylation activity, respectively. In an additional experiment, the influence of the method used to administer Fluosol

on the microsomal cytochrome P-450 activity was investigated (32). Rats received Fluosol by direct intravenous infusion without blood removal or by hemodilution. To differentiate between the effects of Fluosol hemodilution and the physical mechanics of the hemodilution procedure, sham groups were included. These animals underwent the same hemodilution procedure as the groups given Fluosol, except their removed blood was returned. Control groups, which were not pretreated in any manner, were included to show the baseline effects of cannulation on antipyrine disposition.

RESULTS These studies show that hemodilution with 40 ml/kg of Fluosol significantly increased 3-OHME CIF (microsomal cytochrome P-45Ob and P-450 ) by 300% at 48 hours (Figure 1). APAP-S CIF (nonmicrosomal sulfation) was decreased 50% at 48 hours, and ASMZ CIF (nonmicrosomal acetylation) was increased 287% and 162% at 24 and 48 hours, respectively. Complete results of these studies have been published (14,33,34). The method of Fluosol administration (hemodilution versus infusion) had different influences on 3-OHME CI (Figure 2). At 48 hours, 3-OHME CIF was dramatically increased in Fluosol hemodiited animals and unch-q g e d in Fluosol infused animals.

EFFECTS OF MODERATE FLUOSOL-DA HEMODILUTION

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Meta bol ic Form at io n C learances

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DISCUSSION

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Several reports have shown that a single PFC injection induces the cytochrome P-450 isoenzymes in rats and mice (22-25,27-31,35). One series of apers has shown that perfluorodecalin in rats induces the same isoenzymes as phenogarbital 72 hours after injection (24,25,28). However, the extent of induction was not equal; perfluorodecalin induced a larger percentage of cytochrorne P-45Ob/$ than phenobarbital (28). One additional paper has shown that perfluorotributylamine is also a cytochrome P-450 inducing agent (29). Three reports have followed the time course of induction after injection of the PFCs found in Fluosol-DA. The reports of Obraztsov et al. (30) and Armstrong & Lowe (27) showed that the maximum induction of cytochrome P-450 occurred at 3 days, and declined to control levels by 7-10 days. Huang et al. (22) showed a protracted cytochrorne P-450 induction of 200 days. Cytochrome P-4.50 induction has been shown to be perfluorodecdh dose dependent (29); thus the three studies reflected this relationship as the Huang et al. study used a much higher dose of PIT.

In this report, 3-OHME CIF data showed that the phenobarhital inducible cytochrome P-450 isoenzymes were induced at 48 hours after hernodilution, but had returned to control values by 72 hours. With the substantial evidence that cytochrome P-450 contcnt is induced by PFCs at 72 hours, the increase in 3-OHME CIF at 48 hours was thought to be the result of induction. But it is unexpected that the 72 hour values were a t control levels; one would expect the 72 hour values to still be elevated in light of the protracted cytochrome P-450 induction. The method of administration experiment (Fi ure 2) was performed to give insi ht to this unexpected finding. In this experiment, hemodifution did cause an increased 3 - 0 h M E CIF at 48 hours, while sham administration decreased 3-OHME CIF, and infusion of Fluosol had no effect. Thus the increased 3-OHME CIF at 48 hours may not be due to cytochrome P-450 induction hut some transitory phenomenon that occurs only after hemodilution. Several possible " t i Linsitory phenomenon" are listed below.lt may well be that combinations of these explanations are involved either universally, or operative only with a specific substrate. 1. If the PFC particles are taking up the drug (solubilization, adsorption) and enhancing the movement of drug into the hepatocyte smooth endoplasmic reticulum (ER) and Kupffer cell cytosol, then this transitory movement appears to be at its maximum at 48 hours, and returns to normal at 72 hours. The increased acetylation seen at both 24 and 48 hours would then indicate that SMZ appeared at the acetyltransferases in the Kupffer cell cytosol at a faster rate than antipyrine appeared at the hepatocyte smooth ER. The decreased APAP sulfation at 48 hours may be due to a decreased permeabilit of drug movement into the periportal hepatocyte, or a decreased movement to the cytosolic sulfotransferase site. There is evidence that certain drugs bind to the PFC emulsion articles in v i m (36-41), but information about such associations in vivo is not availatle.

2. The PFC particles may not be "solubilizing" the drug directly, but have an indirect effect by changing the sinusoidal plasma membrane permeability. There is no direct evidence of such an alteration. However, one study ind' ated that hernodilution does chan e tissue-to-blood ratios in animals. Using [ i$C]-iodoantipyrine ' as a marker, Ffuosol exchanged rats had an increased tissue-to-"blood" ratio of 1.4 com ared to a 0.8 ratio in unexchanged an' als (42). But the redistribution was attriguted to a rapidly reversible binding of [%I-iodoantipyrine to plasma proteins and to the removal of those plasma proteins during Fluosol exchange. Another report showed that Fluosol caused a decreased number of hepatocytes as well as the hypertrophy of the remaining cells within 1 to 4 days after hernodilution (43.44) Such changes in cellular structure may well alter the plasma membranr: permeability.

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TABLE 1 ENZYME ACTIVITY Cytochrome P-450 (Pb inducible isoenzymes) [ 14,2S,27,28,29,3O,SI ]

MICROSOMES 72h, 150-300% increase

Sulfotransferase Acetaminophen Sulfotransferase [33,51]

72h, 55% decrease

UDP-Glucuronosvltransferase Estimated HPPH'Glucuronidation (51,521

72h. 230% increase

Sulfamethazine acetyltransferase [341

MARKERS 48h, 300% increase

48h, 33% decrease

24h, 74% increase 24-48h, 200-150% increase

3. A change in hepatic activity might occur if the hepatic microcirculation is ~1i:iiiged as the result of hemodilution. Such redistributions have been reported in hepatic (45), cardiac (46), and perfused liver tissue (47). Thus if Illood is diverted from an area of one metabolic capacity to an area of a different metabolic capacity, the net hepatic activity may he altered. An inherent assumption in this proposed mechanism is that the altered microcirculation would be sustained at least 48 hours and return to normal before 72 hours. As the original work on hepati, redistributions indicated (45), the redistributions occurred immediately after hemodilution. There are no reports of altered hepatic redistributions remaining several days after hemodilution. 4. Perhaps an endogenous substance released secondary to hemodilution is

influencing the hepatic activity. Studies in rats have shown that severe Fluosol hernodilution alters the concentrations of many plasma constituents, red and white cell counts, immunological competence, and coagulation res onse (48,49,50). Though detailed information of this nature is not available foiowing moderate Fluosol hernodilution, it is reasonable to assume that similar changes, perhaps abated. are occurring. 5. One other possibility would be that the pharmacokinetics of the metabolite might chan e as the result of hemodilution. CIF is calculated as the molar percentage of the fose appearing as the metabolite in urine collected for 24 hours after drug administration. If the total body clearance of the metabolite does change within that 24 hour period, erroneous estimates of CIF would be obtained. The total body clearance of the parent markers did change as the result of hemodilution (14,33,34); thus, it would seem reasonable that the metabolite's disposition might change as well.

In closing, it is of interest to note that two investigative approaches are being followed regarding the effect of PFC emulsions on hepatic enzymatic function. This report has summarized the "marker" approach using the pharmacokinetics of marker compounds as indicators of enzymatic function. Other references cited in this report chronicle the "microsome" approach of measuring enzymatic concentratioi: or content to quantitate changes in enzymatic function. A comparison of the "marker" ap roach summarized in this report and closely related "microsome" data is given in Table 1. #he time and extent of the altered enzyme activity is given in the body of the tzble. The enzyme activities are grouped

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according to a general pathway, e.g., cytochrome P-450, sulfation, etc. Applicable references are given in the brackets.

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Acute effects of moderate Fluosol-DA hemodilution on hepatic microsomal and nonmicrosomal metabolism in rats.

Fluosol has been shown to alter the disposition of several drugs immediately after its administration. Investigations in this laboratory established t...
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