Pharmacokinetics and Hepatic Extraction of Metoprolol in Rats with Glycerol-Induced Acute Renal Failure

Abstract

The intestinal absorption of orally administered propranolol is essentially complete, with no metabolism of this drug occurring in the gut.1,2) After the oral administration of propranolol, the liver is the principal site of extensive presystemic and systemic metabolism, and less than 1% of the intact drug is found in urine.1,3) However, Bianchetti et al. 4) showed that the area under the concentration-time curve for orally administered propranolol in renal failure patients not on hemodialysis is 7-to 8-fold higher than that in healthy volunteers. We investigated the mechanisms responsible for the increased bioavailability of propranolol in rats with cisplatin-induced renal failure.5) The hepatic intrinsic clearance of propranolol was not significantly altered in rats with renal failure as compared with control rats. However, hepatic firstpass extraction of propranolol was dose-dependent and saturable in both renal failure and control rats, and the initial rate of absorption of the drug from the intestine was significantly greater in rats with renal failure than in control rats. Accordingly, the increased bioavailability of propranolol in rats with cisplatin-induced renal dysfunction is mainly a result of the increased initial absorption rate in the intestine followed by the partial saturation of hepatic first-pass metabolism. 5)Interestingly, the mechanism responsible for the increased bioavailability of propranolol in bilateral ureter-ligated (BUL) rats is different from that in rats with cisplatin-induced renal failure. 2,6) We investigated the pharmacokinetics of propranolol and metoprolol in BUL rats, and found that the rate of intestinal absorption of these drugs was only slightly greater than that in control rats.6) On the other hand, the arterial blood concentrations of propranolol and metoprolol following intra-portal infusion were significantly higher in BUL rats than control rats. 6) Therefore, the increased bioavailability of propranolol and metoprolol in BUL rats was attributed to diminished hepatic first-pass metabolism. The activity of CYP2D2, which is responsible for the metabolism of propranolol and metoprolol in the rat liver, was not altered by BUL, whereas the rate at which NADPH was generated in the liver cytosolic fraction was lower in BUL than control rats. [6][7][8] In addition, endogenous uremic substances are not involved in the reduced hepatic extraction of metoprolol in BUL rats. 9) Accordingly, the decrease in the hepatic metabolic activity and extraction of propranolol and metoprolol in BUL rats is mainly due to the reduced generation of NADPH in the liver.Since the sequence and relative importance of pathophysiological components of acute renal failure in patients are not clearly defined, it is difficult to determine which experimental method for producing renal failure in animals yields results that are most representative of the clinical condition. 10) We consider that the investigation of pharmacokinetics in other renal failure models is indispensable in order to understand the ...

Decreased Lithium Disposition to Cerebrospinal Fluid in Rats with Glycerol-induced Acute Renal Failure

“…In fact, it was demonstrated that the hepatic function of metabolizing therapeutic compounds is changed in rats with experimental renal failure, markedly altering their pharmacokinetics (5,6). In the intestine, the barrier function preventing xenobiotic absorption is decreased in renal failure, resulting in an increase in their intestinal absorption (7,8). These functional changes of the liver and intestine seem to be related to the fact that the expressions of drug-metabolizing enzymes and drug-transporting proteins are significantly altered in renal failure (9)(10)(11)(12).…”

Mechanisms responsible for the altered pharmacokinetics of Bosentan: analysis utilizing rats with bile duct ligation‐induced liver dysfunction

“…was increased more than 10-fold in rats with pretreatment of cyclosporine (50 mg/kg, i.p.) [17]. The effect of 7-day BDL on BBC was also very significant; that is, the mean BBC values in BDL rats were 8.0-and 6.1-fold higher than those in normal rats at infusion rates of 24 and 60 mg/min/ kg, respectively (Figure 1).…”

“…Briefly, whole blood samples (0.1 ml) were mixed with 0.4 ml of distilled water to hemolyse blood cells [16,17]. After acidification with 1.2 ml of 1 M citrate buffer (pH 4.0), the samples were extracted with 5 ml of a mixture of n-butyl chloride and dichloromethane (4: 1, v/v).…”

Altered disposition of drugs in acute renal failure rat models: drug development strategies and perspectives

“…Although reports relating toaltered absorption haven ot been extensivelydocumented in ARF ratmodels,there areafewinstancest od atethats uggest altered absorption:c yclosporine,Y JA-20379-8,diltiazem (CAS 42399-41-7),propranolol,metoprolol (CAS 83-43-2),oltipraz (CAS 64224-21-1),DA-7867,azosemide (CAS 27589-33-9) etc [ 21,25,30,40,41,46,53,55,56].Inthe caseo fcyclosporine in cisplatin,gentamicin,a nd glycerol induced ARF models (Table 2),therewasasignificantr eduction in the rateo fo ralabsorption and itw asalso attributed tothe diminished bile secretion whicho therwisem ayhavecontributed toani mproved solubility of cyclosporine in the intestinalfluids.Thisphenonmenon Glycerol (56-81-5) induced ARF The AUC values of tolbutamide were nearly 40 % lower in ARF rats relative to control rats. This was accompanied by moderate increase in the body clearance of tolbutamide in ARF rats.…”

“…Interestingly,in the uranyln itratem odel,the extentof absorption of cyclosporine afterorald osing was comparable between ARF rats and control rats suggesting thatt hismodel behaved differentlyt hanthe other three ARF models.Anothercompound,Y JA-20379-8,a proton pump inhibitor,wass howntoh aveadecreased absorption ratei nauranyln itratei nduced ARF model [41].Inthe caseo fd iltiazem,itw ass uggested thatan improperoralabsorption mayhaveadditionallycontributed in the uranyln itratei nduced ARF model. In caseo fp ropranol,thereappeared tobetwocontrasting reports toaccountforits enhanced bioavailability in ARF rats.However,the twostudiesu sed differentARF models; the earliers tudyt hatu sed auranyln itrateARF suggested apossible reduction in presystemichepatic elimination [58]and the laterstudythatused acisplatin ARF model indicated ane nhanced intestinalabsorption rateofpropranolol from the gastrointestinaltractof ARF rats [56].Inthe caseo fanotherbeta-blocker,metoprolol,therewasasuggestion thatt he absorption ratewas initiallyincreased followed bys aturation of first-pass elimination [21].Inthe caseo fo ltipraz,therewasadecreased oralabsorption of the compound in ARF rats [30].Inthe caseo fDA-7867,aminordecreased absorption mayhavecontributed tothe reduced exposure [25]. Inthe caseo fazosemide,therewaspronounced intestinalabsorption of the drugi nARF rats [40], contrary to the reduced gastricemptying time reported forcyclosporine in ARF rats [55,56].…”