Placental drug transfer: effects of gestational age and species.

The available evidence suggests that for most drugs, adverse effects in the fetus may vary with gestational state and among species due to: (i) changes in the fetal exposure to the drug (i.e. due to changes in the pharmacokinetics of the drug in the mother and/or the fetus), or to (ii) changes in the susceptibility of the fetus to the drug. The fetal exposure to a drug during gestation is influenced more by the varying capacity of mother and/or fetus to eliminate the drug than by any intrinsic 'barrier' phenomenon at the placenta. Although differential maternal/fetal protein binding, active transplacental transport processes and 'ion-trapping' effects may influence the fetal exposure of some drugs, the main mechanisms by which fetal exposure may be modulated during pregnancy are via the capacity for irreversible drug elimination--by the fetus or, less often, by the placenta. The susceptibility of a fetus to adverse drug reactions is determined by the ontogeny of vital processes and the nature of the interaction between the drug and the process. Hence 'gestational state' and 'species' dependent differences in adverse drug effects, in the presence of a constant level of exposure of drug, reflect the time dependent appearance of these processes and the differences in ontogeny of the processes among species. At present, no studies have attempted to relate the measured fetal drug exposure to the intensity of a drug response at different stages of gestation or among species. Although there is a dearth of information in this field, it is apparent that in all species the placentas of all species pose little obstruction to the passage of xenobiotics (including drugs), to the fetus. The consequence of this exposure will depend on a myriad of pharmacokinetic and pharmacodynamic considerations for a given substance in a given species. Hence the outcome cannot be predicted, but must be empirically determined. Extrapolation of findings among different drugs, species and gestational states must be undertaken with caution, recognizing the above considerations and limitations.

Rectal administration of sodium valproate in status epilepticus.

Six patients suffering from status epilepticus were refractory to parenteral treatment with either diazepam, amobarbital or both, and were given sodium valproate 200 to 800 mg every 6 hours. The drug was administered rectally as 200 mg lipid-based suppositories, thereby avoiding impaired absorption, which occurs in the presence of paralytic ileus. Plasma levels of sodium valproate in all patients reached the therapeutic range within 36 hours of starting therapy. Seizures were totally controlled in five patients and a 75 percent reduction was noted in the sixth. In two patients, the route of administration was changed from rectal to an equivalent oral dose with continuing control of seizures and minimal change in plasma levels, suggesting that bioavailability is similar for the two forms of the drug. The rectal route of administration was effective in achieving systemic absorption of sodium valproate in the treatment of status epilepticus.

The effect of malaria infection on primaquine elimination in the isolated perfused rat liver.

Most antimalarial drugs are eliminated by hepatic metabolism. However, the influence of malaria infection on the hepatic elimination of these drugs has not been examined. In the present study the elimination of the antimalarial primaquine has been examined in isolated perfused rat livers (IPRL) of malaria-infected Sprague-Dawley rats (90-110 g) (MI group; N = 6) and age- and weight-matched healthy rats (control group; N = 7). IPRL preparations for the MI group were established 12-15 days after rats were infected with merozoites of Plasmodium berghei (150 X 10(6) parasites/ml; 0.2 ml i.p.). At the time of study there was marked variation in the degree of parasitaemia achieved in the rats used in the MI group, from 2 to 27% of erythrocytes being infected. Livers were isolated using standard techniques and perfused at 10 ml/min in a 100 ml recycling system for 4 hr. In the control group, the perfusate disappearance of primaquine was biphasic with a mean t1/2 beta of 0.77 +/- 0.10 hr. This was prolonged in the MI group (mean t1/2 beta = 1.06 +/- 0.09 hr; P less than 0.05). There was no significant difference in the volumes of distribution of primaquine between the MI group (mean = 320 +/- 73 ml) and the control group (mean = 284 +/- 79 ml). Although there was a trend to lowered primaquine clearance in the MI group (mean 217 +/- 26 ml/hr), it was not significantly different from that seen in the control group (mean = 277 +/- 42 ml/hr; 0.10 less than P greater than 0.05). However, there was an inverse linear correlation between primaquine clearance and the percentage parasitaemia (r = 0.722, P less than 0.05). These results suggest that the extent to which primaquine elimination had been compromised was related to the severity of malaria infection, and that in severe infections reduced efficiency of elimination raises the possibility of drug toxicity.

Synergistic effects of hypoxia and fasting on harmol elimination in the isolated perfused rat liver.

In isolated hepatocytes the availability of intracellular glucose appears to be a key factor controlling the rate of xenobiotic glucuronidation during hypoxia. This study in the isolated perfused rat liver examines the effect of both a 24-hr fast and removal of glucose (8 mM) from liver perfusate on the elimination of bolus doses of harmol (20 mumol) under normoxic and hypoxic conditions. In the preparations used in these experiments, harmol glucuronide is the major metabolite (greater than 80%) with the remainder being sulphate. During normal oxygenation, in the livers from fed rats, harmol was rapidly eliminated (t1/2 = 4.2 +/- 0.4 min; mean +/- SD, N = 4). Fasting led to a small reduction in harmol elimination rate (t1/2 = 5.6 +/- 0.4 min; P less than 0.025) while removal of glucose from perfusate made no difference in either fed or fasted preparations. In the same livers, a second bolus dose of harmol was given during hypoxia. This produced a modest decline in harmol elimination in fed rats (t1/2 = 7.1 +/- 2.0 min; P less than 0.05). However, in fasted rats there was a striking reduction in harmol elimination (t1/2 = 109.8 +/- 54.0 min; P less than 0.025). The removal of glucose from perfusate made no significant difference to these results (t1/2 = 253 +/- 209 min in fasted preparations, P greater than 0.1). In all preparations, reoxygenation resulted in a rapid recovery of drug elimination. We conclude that nutritional state is important in determining the impact of hypoxia on harmol elimination by the liver. This study suggests that clinically significant reductions in xenobiotic glucuronidation are most likely to occur in poorly nourished or fasted subjects who became hypoxaemic.

The effects of primaquine stereoisomers and metabolites on drug metabolism in the isolated perfused rat liver and in vitro rat liver microsomes.

The effect of the antimalarial drug primaquine, its stereoisomers and its proposed metabolites, on the metabolism of substrates for mixed function oxidase, has been studied in isolated perfused rat livers (IPRL) and/or in vitro microsomal suspension. Following acute administration to an IPRL preparation, racemic primaquine produced a dose related reduction in the hepatic clearance of antipyrine which at the highest dose of primaquine (5.0 mg) represented a decrease to 46% of control values. Antipyrine clearance was reduced to a comparable extent by the (+) and (-) isomers and the racemic mixture (each at a dose of 2.5 mg) with mean reductions of 45, 49 and 47%, respectively. These changes in clearance were reflected by significant increases in half-life relative to control. The apparent volume of distribution of antipyrine was unchanged in all experiments. Racemic primaquine and its (+) and (-) isomers were equipotent in inhibiting aminopyrine N-demethylase activity, producing reductions of 56, 59 and 55%, respectively, relative to control values. These three compounds also produced corresponding reductions of 73, 58 and 73% in ethoxyresorufin O-deethylase activity. The N-acetyl and 5-hydroxy derivative of primaquine produced inhibitory effects comparable to that seen for the parent drug. In contrast the carboxylic acid metabolite of primaquine, 6-desmethylprimaquine and 5-hydroxy-6-desmethyl primaquine did not influence aminopyrine N-demethylase activity. These results indicate that the propensity to inhibit drug metabolism by these primaquine related substances, is influenced by functional group substitution rather than the optical activity of the parent drug.

Effect of hypoxia on oxidative and reductive pathways of omeprazole metabolism by the isolated perfused rat liver.

The effect of hypoxia on the elimination of omeprazole, a potent inhibitor of gastric acid secretion, was studied in the isolated perfused rat liver. During normal oxygenation, a 10 mg bolus dose was eliminated rapidly (T 1/2 beta = 8.0 +/- 1.1 min; mean +/- S.E.M., N = 4), while under hypoxic conditions T 1/2 beta was increased to 81.6 +/- 5.4 min (P less than 0.01). Upon reoxygenation, T 1/2 beta returned to 9.6 +/- 1.3 min. During hypoxia, perfusate concentrations of an oxidative metabolite (the sulphone) were reduced by 68%, while those of the reductively-generated sulphide increased 4-fold. With reoxygenation, both formation and elimination of the sulphone were increased, while the sulphide, which had accumulated during the hypoxic period, was eliminated rapidly. These findings were duplicated in steady-state experiments, in which omeprazole clearance during hypoxia fell by at least 70%, and sulphide concentrations in perfusate rose from undetectable levels to 200 ng/ml (at least a 10-fold increase). Sulphone concentrations did not change with hypoxia, consistent with a reduction in both its formation and elimination rates. We conclude that the hepatic elimination of omeprazole is severely retarded by hypoxia, but that this effect is promptly reversed by reoxygenation. The increased formation of reductive metabolite during hypoxia is not of sufficient magnitude to sustain the normal hepatic elimination of omeprazole.

Oxygen dependence of salbutamol elimination by the isolated perfused rat liver.

Although impairment of drug metabolism by severe hypoxia is well documented in perfused liver preparations, the degree of hypoxia required to produce inhibition of drug elimination pathways in the intact liver has not been defined. In this study, in the isolated perfused rat liver, we examined the relationship between the rate of hepatic oxygen supply and the elimination rate of the drug salbutamol, which in the rat liver is eliminated largely by glucuronidation. Livers (N = 15) from male Sprague-Dawley rats were perfused in a non-recycling design with 10% human red cells in a Krebs-Henseleit electrolyte solution. Salbutamol elimination was examined during normal oxygenation (perfusate equilibrated with 100% O2; mean O2 delivery 3.21 mumol/min/g liver), at a given lower rate of oxygen delivery (achieved by producing different mixtures of N2 with O2 in the perfusate oxygenator) and after reoxygenation. In these experiments, hepatic clearance of salbutamol (perfusate concentration 50 ng/ml) was essentially independent of oxygen delivery above a rate of 2.0 mumol/min/g liver; below this level, clearance fell linearly as O2 supply was reduced. In all livers, reoxygenation restored drug elimination to control levels. In further experiments using a recycling design (N = 22), the effect of hypoxia on salbutamol elimination was found to be very similar. In recycling normoxic experiments (N = 3), the glucuronide metabolite was detected in perfusate and bile, but no sulphate metabolite was detected. While previous studies indicate that elimination of some oxidatively metabolised substrates is very sensitive to reductions in hepatic oxygenation, the present study shows that, in the isolated liver, large reductions in hepatic oxygen supply were required to produce significant impairment of the glucuronidation-dependent elimination of salbutamol.

Intracellular binding is an important determinant of the avid hepatic uptake of the high clearance drug omeprazole.

The contribution of intracellular storage to hepatic uptake of the high clearance drug, omeprazole, was examined in the recirculating isolated perfused rat liver preparation. Following injection of [3H]omeprazole (7.5 microCi, 5 mg) into the portal vein over 1 min, livers were perfused for 5 min (N = 3) or 30 min (N = 3) and then homogenized at 4 degrees and fractionated by differential centrifugation. Radiolabelled omeprazole and metabolites were determined by scintillation counting of fractions of eluant from HPLC. Seventy per cent of drug had been taken up by the liver at 5 min and 85% at 30 min, with unchanged drug representing 43 and 7.4%, respectively, of drug taken up. At both times, 70-75% of intracellular unchanged drug and the major metabolites were located in the cytosol, and the cytosol:perfusate concentration ratio was approximately 10:1. Mitochondrial, lysosomal and microsomal fractions contained relatively little drug. Extensive cytosolic binding of omeprazole therefore contributes substantially to the initial avid hepatic first-pass uptake of this drug.

Decreased hepatic elimination of pyrimethamine during malaria infection. Studies in the isolated perfused rat liver.

The elimination of the antimalarial drug pyrimethamine was studied in isolated liver preparations from young rats (80-100 g) infected with merozoites of Plasmodium berghei two weeks earlier. Perfusate half-life of pyrimethamine was increased in livers from M.I. rats (t1/2 beta control group = 56 +/- 11 min vs M.I. group = 101 +/- 12, P less than 0.01), reflecting a decrease in hepatic clearance (3.6 +/- 1.1 ml/min vs 1.9 +/- 0.5 ml/min, P less than 0.01). There was no significant difference in volume of distribution between livers from M.I. and control groups. Intrahepatic concentration of unchanged drug at 3 hr was 4-5-fold greater in livers from infected rats (control group = 4725 +/- 2287 ng/ml vs M.I. group = 22,324 +/- 6824 ng/ml), while liver: perfusate concentration ratios were not significantly different (control group = 30.8 +/- 24.1 vs M.I. group = 35.6 +/- 20.3). We conclude that the hepatic elimination of pyrimethamine is substantially impaired in the malaria-infected rat.

The disposition of pyrimethamine in the isolated perfused rat liver.

We have investigated the disposition of pyrimethamine base in the isolated perfused rat liver (IPRL) preparation after the administration of pyrimethamine (0.5 mg, 5 microCi). In the first half hour of the study, pyrimethamine underwent marked hepatic uptake, thereafter perfusate plasma drug levels declined monoexponentially with a half life (t 1/2) of 3.0 +/- 1.0 hr. Area under the perfusate plasma concentration/time curve (AUC)0----infinity was 6.9 +/- 1.9 microgram/hr/ml. Pyrimethamine was found to be a low clearance compound (78.4 +/- 25.3 ml/hr identical to 8.6% of liver perfusate flow) with a large volume of distribution (267.5 +/- 55.3 ml) in the IPRL. The combined AUCS(0----5hr) for pyrimethamine (AUC 4.8 +/- 0.5 microgram/hr/ml) and pyrimethamine 3-N-oxide (AUC0----5hr 0.9 +/- 0.6 microgram/hr/ml) accounted for 57% of the total AUC0----5hr of [14C] radioactivity (10.0 +/- 2.6 micrograms/hr/ml). This indicates the presence of metabolites of pyrimethamine as yet unidentified in the perfusate. Biliary excretion of [14C] during the course of the IPRL preparations was extensive (29.0 +/- 10.3%) though only a small proportion was due to pyrimethamine and the 3-N-oxide metabolite. The majority of radioactivity in the bile was attributable to highly polar, but unidentified metabolites of pyrimethamine. At the conclusion of each experiment (5 hr), a significant proportion of [14C] radioactivity was recovered from the livers (22.9 +/- 5.3%). Subsequent HPLC analysis of the liver tissue indicated this to be unchanged pyrimethamine, with trace levels of the 3-N-oxide metabolite. Sub-cellular fractionation of the homogenized livers revealed the most pronounced localisation of pyrimethamine to be in the lipid rich 10,000 g pellet (13.0 +/- 2.6%), the remainder being distributed equally between the 105,000 g pellet and supernatant. Neither pyrimethamine, [14C] radioactivity, nor pyrimethamine 3-N-oxide were extensively taken up by red cells throughout the study. Therefore, the large volume of distribution (267.5 +/- 55.3 ml) underlines the extent of pyrimethamine localisation in the liver.

High-pressure liquid chromatographic determination of ranitidine, a new H2-receptor antagonist, in plasma and urine.

An assay is described for the determination of a new H2-receptor antagonist, ranitidine, and its desmethyl metabolite in human plasma and urine. Alkalinized plasma or urine was extracted with methylene chloride, the organic phase was evaporated, and the reconstituted residue was analyzed by high-pressure liquid chromatography using a reversed-phase column. Two other identified metabolites of ranitidine, the S-oxide and N-oxide, were separated chromtographically from both ranitidine and the desmethyl metabolite. However, these metabolites could not be quantitative due to poor analytical recovery and interference from endogenous components. The sensitivity limits were 5 ng/ml for ranitidine and 15 ng/ml for desmethylranitidine. Plasma samples from two volunteers who were given oral ranitidine (0.1, 0.2, and 0.4 mg/kg) at 1-week intervals were assayed. Peak levels of 30--130 ng/ml were achieved between 40 and 120 min after dosage, followed by an elimination half-life of 2.9-3.9 hr. Plasma levels of ranitidine were still detectable at 8 hr but were below the sensitivity of the assay by 24 hr. Plasma levels of the desmethyl metabolite were seldom above the threshold sensitivity of the assay. Urinary excretion of unmetabolized ranitidine accounted for 77% of the administered dose, whereas only 4% appeared as desmethylranitidine.

Propranolol elimination as described by the venous equilibrium model using flow perturbations in the isolated perfused rat liver.

The kinetics of hepatic elimination of the high-clearance drug propranolol has been interpreted in a previous study from our laboratory, in which propranolol protein binding was varied, to conform to the venous equilibrium model. In another study by a different group, in which perfusate flow was varied, propranolol kinetics was interpreted to conform to the sinusoidal model. In the present study, we investigated the possibility that this discrepancy is due to the use of the two different discriminants, flow and protein binding, in the two studies. In eight livers, perfused in a recirculating design, steady-state elimination of propranolol (infused at a rate of 22.8 micrograms/min) was examined at perfusate flow rates of 16 and 32 mL/min. Hepatic outflow concentration was independent of perfusate flow rate, while the logarithmic average concentration was significantly lower at the higher flow. These data conform to the venous equilibrium model and are not consistent with the sinusoidal model. This shows that the outcome of these modeling experiments does not depend on the experimental approach used, and reaffirms that the venous equilibrium model is appropriate for propranolol under the conditions studied.

High-pressure liquid chromatographic determination of cimetidine in plasma and urine.

An assay is described for the determination of the H2-receptor antagonist, cimetidine, in human plasma and urine. Alkalinized plasma or urine was extracted with methylene chloride, the organic phase was evaporated, and the reconstituted residue was analysed by high-pressure liquid chromatography (HPLC) using a reversed-phase prepacked plastic column housed in a radial compression module. The metabolite, cimetidine sulfoxide, was identified but could not be quantitated due to interference from the solvent front. The sensitivity limit of the assay was 25 ng/ml. The assay was applied to the measurement of plasma and urine samples in a pilot pharmacokinetic study. Cimetidine was substantially absorbed and rapidly eliminated (plasma elimination half-life of 112-130 min). Plasma cimetidine concentrations could be measured to 12 hr after a 200-mg dose (iv or oral), but they were below the sensitivity of the assay by 24 hr. Urinary excretion of unmetabolized cimetidine accounted for 40-50% of the administered dose in the first 12 hr. This assay is simpler and more sensitive than those previously described, and it is suitable for the measurement of cimetidine in plasma and urine of subjects receiving doses appropriate for clinical use.

Influence of maternal plasma protein binding on fetal unbound plasma concentration of propranolol in the pregnant ewe.

According to theory, for a drug of nonrestrictive, flow-limited clearance, a change during pregnancy of the unbound fraction (fu) of drug in maternal plasma should cause a change in steady-state unbound plasma drug concentration (Cu) in maternal plasma, which should also cause a change in fetal Cu. This theory was examined in 14 chronically cannulated, unanesthetized pregnant ewes in which 28 separate experiments were performed during the latter part of gestation. An initial bolus dose and 3-h constant rate infusion of propranolol were administered via the maternal jugular vein and steady-state maternal and fetal carotid arterial plasma total and unbound propranolol concentrations were measured. Fetal Cu (32 +/- 21 ng/mL) was significantly less than maternal Cu (78 +/- 52 ng/mL), due to previously demonstrated fetal hepatic extraction of propranolol. Notwithstanding fetal elimination, there was a significant correlation between fetal Cu and maternal Cu (r = 0.41, p less than 0.025). There was also a strong correlation between fetal Cu and the maternal unbound fraction of drug (fu; r = 0.75, p less than 0.001). We conclude that for propranolol, a drug of nonrestrictive, flow-limited clearance, changes in maternal fu can have a significant influence on fetal Cu, and therefore would be expected to influence the pharmacological effect of the drug in the fetus.

Disposition of the diastereoisomers quinine and quinidine in the ovine fetus.

The disposition of the diastereoisomers quinine and quinidine was investigated in the near-term pregnant ewe. Five sheep were administered quinine and quinidine separately in random order by a combination of bolus and 30-h iv infusion. On a subsequent occasion, four of the five sheep were also administered the two drugs simultaneously. After separate dosage, systemic clearance of quinine tended to be greater than that of quinidine (714 +/- 299 versus 422 +/- 146 mL/min, p = 0.08). Maternal renal clearance exhibited no stereoselectivity and represented less than 2% of total clearance. Simultaneous administration did not alter the disposition of either drug in the mother. After separate dosage, fetal total concentrations (Cf) of quinine and quinidine were substantially lower than maternal total concentrations, as reflected in Cf:Cm ratios of 0.15 +/- 0.06 versus 0.10 +/- 0.08, respectively. Similarly, fetal unbound concentrations (Cfu) were substantially lower than maternal unbound concentrations (Cmu; Cfu/Cmu = 0.46 +/- 0.09 for quinine and 0.23 +/- 0.09 for quinidine). This indicates the presence of fetal elimination of both isomers. Fetal renal clearances of quinine and quinidine were similar (0.34 +/- 0.24 mL/min versus 0.38 +/- 0.24 mL/min) and less than that of endogenous creatinine, indicating the absence of net renal tubular secretion. After simultaneous dosage of quinine and quinidine, Cf:Cm (0.48 +/- 0.24 and 0.31 +/- 0.19, respectively) and Cfu:Cmu (0.73 +/- 0.14 and 0.52 +/- 0.20, respectively) were greater than for separate dosages. Fetal renal clearance of both drugs was unchanged, suggesting that the higher Cfu:Cmu ratios after simultaneous dosage were due to mutual inhibition of the fetal metabolism of these drugs.

Placental transfer of ranitidine during steady-state infusions of maternal and fetal sheep.

The placental transfer of ranitidine was studied at pharmacokinetic steady state in anesthetized, full-term, pregnant sheep. Ranitidine was administered to the ewe in three preparations and to the fetus in three other sheep. In all experiments, dose size was based on the combined maternal-fetal weight. Steady-state plasma levels were reached within 4 hr by using an initial intravenous bolus dose followed by continuous infusion. Following maternal dosage, the mean maternal (jugular vein) steady-state concentration (CMss) at 4 hr was 842 +/- 66 ng/ml (SEM), the mean fetal (carotid artery) steady-state concentration (CFss) was 26.5 +/- 4.2 ng/ml, and the mean fetal umbilical venous steady-state concentration was 28.9 +/- 3.5 ng/ml. Both the fetal and umbilical plasma concentrations were significantly less than the maternal plasma concentrations (p less than 0.01). With fetal dosage, mean CMss was 414 +/- 42 ng/ml at 4 hr and was significantly less than the mean CFss value at the same time, which was 6890 +/- 360 ng/ml (p less than 0.005). Ranitidine was not bound extensively to plasma proteins in the ewe or the fetus (range 12-55% bound). The reversal of the CMss/CFss gradient with the change from maternal to fetal administration and the low binding of the drug shows that the gradient following maternal dosage cannot be explained by ion-trapping or differential plasma protein binding. As active placental transport is considered unlikely, the low fetal plasma concentrations are probably due to the presence of significant fetal elimination of ranitidine. Furthermore, the substantial gradient between maternal and umbilical venous plasma concentrations suggests that placental elimination of ranitidine should also be considered.

Quinine impairs quinidine clearance in rat perfused liver.

We have examined the disposition of the cinchona alkaloids quinine and quinidine in the rat recirculating isolated perfused liver preparation. When administered as separate 1 mg doses, the hepatic clearances of quinine and quinidine were similar to the hepatic perfusate rate of 10 mL min-1. When 1 mg of each was administered simultaneously, mean hepatic clearance of quinine was unchanged (9.00 +/- 2.20 mL min-1 separate dosage, n = 7; 6.87 +/- 1.77 mL min-1 simultaneous dosage, n = 7; P > 0.05). By contrast, mean hepatic clearance of quinidine was reduced significantly by concomitant quinine (10.6 +/- 1.72 mL min-1 separate dosage, n = 7; 4.82 +/- 1.25 mL min-1 simultaneous dosage, n = 7; P < 0.05). There was no significant difference in volumes of distribution when each alkaloid was administered separately (131 +/- 46 mL quinine, 129 +/- 21 mL quinidine; P > 0.05) but concomitant quinine administration increased quinidine volume of distribution to 169 +/- 30 mL (P < 0.05). Four further experiments with simultaneous dosages of 0.5 mg of each alkaloid produced similar findings, indicating that the interactions did not derive from nonlinear drug disposition.

The effect of some benzimidazoles on the disposition of antipyrine and tolbutamide from the rat isolated perfused liver.

The anthelmintic benzimidazoles, mebendazole, albendazole and flubendazole have been screened for any propensity to alter the disposition of antipyrine and tolbutamide in the rat isolated perfused liver preparation. The benzimidazoles were added as a 2.5 mg bolus dose into the perfusate reservoir 5 min before the administration of either antipyrine or tolbutamide. Neither mebendazole or albendazole produced any significant effect on the pharmacokinetics of either of the substrate drugs. In contrast, flubendazole significantly decreased the clearance of antipyrine (by 40%) indicating inhibition of mixed function oxidase activity. However, flubendazole did not alter the disposition of tolbutamide. The results suggest that not all benzimidazoles inhibit hepatic drug metabolizing enzymes and that different forms of cytochrome P-450 are involved in the metabolism of antipyrine and tolbutamide.

Effect of omeprazole and polyethylene glycol-400 on antipyrine elimination by the isolated perfused rat liver.

The effect of the substituted benzimidazole, omeprazole, a potent inhibitor of gastric acid secretion, on the hepatic elimination of antipyrine was studied in the rat isolated perfused liver. Bolus dosage (10 mg in 100 ml perfusate) and infusions (1 microgram ml-1 perfusate concentrations) of omeprazole in its solvent, polyethylene glycol-400 (PEG-400), reduced antipyrine clearance by approximately one third (P less than 0.05). PEG-400 alone caused a 15% decrease in antipyrine clearance (P greater than 0.10), indicating that the effect seen with omeprazole was at least partly due to the vehicle of dissolution. A significant but mild choleresis was noted in all preparations (P less than 0.01) exposed to PEG-400. We conclude that the effect of omeprazole on hepatic drug elimination in patients warrants further study.

Pyrimethamine pharmacokinetics and its tissue localization in mice: effect of dose size.

The plasma pharmacokinetics and mass fate of [14C]pyrimethamine were investigated in the mouse, following dosage with 12.5, 25, 50, and 75 mg kg-1 (i.p.). Peak plasma concentrations of pyrimethamine were reached between 1 and 2 h and then declined monoexponentially. The mean values for AUC0----30 h increased linearly in relation to the administered dose of pyrimethamine (r = 0.979, P less than or equal to 0.001). The mean values for intraperitoneal clearance and half-life were not significantly different between dose groups, indicating that the plasma pharmacokinetics of pyrimethamine were independent of dose. The percentage of the administered dose excreted in urine as pyrimethamine (1.3-3.5%) and 14C-radioactivity (21.7-29.1%) did not change with increasing dose. In contrast, the cumulative percentage of the dose excreted as 14C-radioactivity in faeces (16.7-22.8%) after the three highest doses 25, 50 and 75 mg kg-1 was significantly less than that seen with the lowest dose of 12.5 mg (50.3%). This suggests extensive biliary excretion of radioactivity, and that the capacity of this process may have been exceeded with the highest doses. Seven days after the administration of each of the three highest doses, a significantly greater percentage of [14C]pyrimethamine was localized in the soft tissues; i.e. heart, lung and kidney (7.8-13.8%), gut (5.4-9.4%) and particularly the liver (25.0-27.9%) when compared with the lowest dose of the drug (1.2, 1.0, 0.3% respectively). Following each dose, between 85 and 97% of the administered radioactivity was accounted for.(ABSTRACT TRUNCATED AT 250 WORDS)