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The capacity of arthropod populations to adapt to long-term climatic warming is uncertain. Here, we combine theory and extensive data on diverse arthropod taxa to show that their rate of thermal adaptation to climatic warming will be constrained in two fundamental ways. First, the rate of thermal adaptation is predicted to be limited by the rate of shift in the temperature of peak performance of four life-history traits in a specific order: juvenile development, adult fecundity, juvenile mortality, and adult mortality. Second, thermal adaptation will be constrained due to differences in the temperature of peak performance among these four traits, which are expected to persist because of trade-offs. By compiling a new global dataset of 61 diverse arthropod species, we find strong evidence that contemporary populations have indeed evolved under these constraints. Our results provide a basis for using relatively feasible trait measurements to predict the adaptive capacity of diverse arthropod populations to climatic warming.

Dispersal behaviour plays a key role in social organisation, demography, and population genetics. We describe dispersal behaviour in a population of African wild dogs (Lycaon pictus) in Kenya. Almost all individuals, of both sexes, left their natal packs, with 45 of 46 reproductively-active “alpha” individuals acquiring their status through dispersal. Dispersal age, group size, and distance did not differ between males and females. However, only females embarked on secondary dispersal, probably reflecting stronger reproductive competition among females than males. When dispersing, GPS-collared wild dogs travelled further than when resident, both in daylight and by night, following routes an order of magnitude longer than the straight-line distance covered. Dispersers experienced a daily mortality risk three times that experienced by adults in resident packs. The detailed movement data provided by GPS-collars helped to reconcile differences between dispersal patterns reported previously from other wild dog populations. However, the dispersal patterns observed at this and other sites contrast with those assumed in published demographic models for this endangered species. Given the central role of dispersal in demography, models of wild dog population dynamics need to be updated to account for improved understanding of dispersal processes.

Vectors are responsible for the transmission of many important endemic and emerging diseases. The functional traits of these animals have important consequences for pathogen transmission, but also for fitness and population dynamics of the vectors themselves. Increasing empirical evidence suggests that vector traits vary significantly at time scales relevant to transmission dynamics. Currently, an understanding of how this variation in key traits impacts transmission is hindered by a lack of empirical data as well theoretical methods for mechanistically incorporating traits into transmission models. Here, we present a framework for incorporating both intrinsic and environment-driven variation in vector traits into empirical and theoretical vector-borne disease research. This framework mechanistically captures the effect of trait variation on vector fitness, the correlation between vector traits, and how these together determine transmission dynamics. We illustrate how trait-based vector-borne disease modelling can make novel predictions, and identify key steps and challenges in the construction, empirical parameterization and validation of such models. Perhaps most importantly, this framework can also be used to prioritize data collection efforts.

The following multiprocessor scheduling problem was motivated by scheduling maintenance periods for aircraft. Each maintenance period is a job, and the maintenance facilities are machines. In this context, there are very few different types of maintenances performed, so it is natural to consider the problem with only a small, fixed number C of different types of jobs. Each job type has a processing time, and each machine is available for the same length of time. A machine can handle at most one job at a time, all jobs are released at time zero, there are no due dates or precedence constraints, and preemption is not allowed. The question is whether it is possible to finish all jobs. We call this problem the Multiprocessor Scheduling Problem with C job lengths (MSPC). Scheduling problems such as MSPC where we can partition the jobs into relatively few types such that all jobs of a certain type are identical are often called high-multiplicity problems. High-multiplicity problems are interesting because their input is very compact: The input to MSPC consists of only 2C + 2 numbers. For the case C = 2 we present a polynomial-time algorithm. We show that this algorithm guarantees a schedule that uses the minimum possible number of different one-machine schedules, namely three. Further, we extend this algorithm to the case of machine-dependent deadlines (uniform parallel machines), to a multi-parametric case (that contains the case of unrelated parallel machines), and to some related covering problems. Finally, we give some counterexamples showing why our results do not extend to the case C > 2.

Hepatitis B virus (HBV) has been demonstrated in bile duct epithelial cells (BDEC) during chronic infection. The persistence of virus in BDEC may play an important role in disease pathogenesis, and may be at least partly responsible for the relapse phenomenon observed in antiviral treatments using nucleoside analogues. The aims of this study were to examine the morphological changes within the liver in the duck hepatitis B model following bile duct ligation (BDL), and to assess the effect of biliary hyperplasia upon viral DNA and proteins. Seven-day-old ducklings, congenitally infected with the duck hepatitis B virus (DHBV), were subject to BDL. The pathological and virological changes were then followed at 5, 10, 15, and 20 days after ligation. All results were compared with age-matched unligated control birds congenitally infected with DHBV. To assess the early morphological changes, additional animals were sacrificed at 1, 2, 3, and 4 days post-BDL. The proportion of DHBV-infected BDEC, was examined by immunohistochemistry and in situ hybridization. BDL induced rapid biliary hyperplasia, with a doubling time for BDEC of 1.3 days. The proliferated BDEC displayed immunohistochemical features identical to resting BDEC. More than 50% of BDEC in unligated controls, and more than 46% of proliferated BDEC in ligated animals were positive for DHBV DNA and structural proteins. The intensity of immunohistochemical staining and in situ hybridization signal in the BDEC was consistently greater than that of the hepatocytes, both before and after BDL. BDL induces biliary hyperplasia in the duck model, and BDEC division does not reduce the viral burden in infected cells.

Previous studies of the effect of albumin on initial uptake of ligands by isolated cell suspensions or cultures found that the apparent uptake for unbound ligand appeared larger in the presence of binding to the albumin than when albumin was absent. Furthermore, when ligand and albumin were increased in a fixed molar ratio, uptake appeared to be competitively inhibited by the excess albumin. We examined the kinetics underlying this apparent facilitation phenomenon by incorporating unbound fraction of ligand in the medium (fu1) into the general model for diffusion between two compartments. The analysis showed that even in the absence of facilitation by albumin, the apparent rate constant for uptake of unbound ligand (k/fu1) increases as albumin concentration increases but the uptake clearance of unbound ligand remains constant. This theoretical analysis was verified experimentally by measuring the effect of albumin on uptake rates of 14C-taurocholate (12, 24, 48, 60, and 96 microM, with and without 0.87 mM albumin) in a nonphysiological system consisting of two solutions separated by a cellulose membrane. Moreover, when the taurocholate and albumin concentrations were increased in a fixed molar ratio of 0.06 (taurocholate 12-96 microM, albumin 0.2-1.6 mM), the initial uptake rate exhibited the same nonlinear pattern as the previous studies that used living cells. This pattern was due not to saturation of a putative albumin receptor but simply to the concomitant decrease in fu1 which tended to offset the increase in uptake rate due to the increasing total taurocholate concentration. The model was also used to evaluate published data describing the effect of albumin on the uptake of iopanoic acid by cultured hepatocytes. In accordance with the model, k1/fu1 increased as albumin concentration increased, but uptake clearance was independent of albumin concentration. Therefore, the kinetic pattern found in this and other studies with isolated cell suspensions or cultures argues against a special role for albumin in facilitating cellular ligand uptake.

After the transition from in utero to newborn life, the neonate becomes solely reliant upon its own drug clearance processes to metabolise xenobiotics. Whilst most studies of neonatal hepatic drug elimination have focussed upon in vitro expression and activities of drug-metabolising enzymes, the rapid physiological changes in the early neonatal period of life also need to be considered. There are dramatic changes in neonatal liver blood flow and hepatic oxygenation due to the loss of the umbilical blood supply, the increasing portal vein blood flow, and the gradual closure of the ductus venosus shunt during the first week of life. These changes which may well affect the capacity of neonatal hepatic drug metabolism. The hepatic expression of cytochromes P450 1A2, 2C, 2D6, 2E1 and 3A4 develop at different rates in the postnatal period, whilst 3A7 expression diminishes. Hepatic glucuronidation in the human neonate is relatively immature at birth, which contrasts with the considerably more mature neonatal hepatic sulfation activity. Limited in vivo studies show that the human neonate can significantly metabolise xenobiotics but clearance is considerably less compared with the older infant and adult. The neonatal population included in pharmacological studies is highly heterogeneous with respect to age, body weight, ductus venosus closure and disease processes, making it difficult to interpret data arising from human neonatal studies. Studies in the perfused foetal and neonatal sheep liver have demonstrated how the oxidative and conjugative hepatic elimination of drugs by the intact organ is significantly increased during the first week of life, highlighting that future studies will need to consider the profound physiological changes that may influence neonatal hepatic drug elimination shortly after birth.

Congestive heart failure has been shown to affect oxidative drug metabolism, however, there has been little study of its effects on drug conjugation. Using the isolated perfused livers from rats with right ventricular failure (RVF) due to pulmonary artery constriction, we studied the effects of RVF on hepatic elimination of p-nitrophenol (PNP) under controlled flow and oxygen delivery conditions. Hepatic clearance of the drug was found to be significantly impaired in RVF as compared with the sham group (0.80 +/- 0.23 versus 1.28 +/- 0.26 ml/min/g of liver). The impairment of PNP clearance in RVF occurred in parallel with significant reduction in metabolic formation clearance of p-nitrophenyl-beta-D-glucuronide; the major metabolite of PNP (0.51 +/- 0.12 versus 1.03 +/- 0.26 ml/min/g of liver). The intrinsic drug-glucuronidation capacity of livers was evaluated by measuring the microsomal content and activity of the UDP-glucuronosyltransferase(s) (UDP-GT) toward p-nitrophenol. There was no significant difference between sham and the RVF groups in either the content or the activity of the UDP-GT. The latency of the UDP-GT enzymes in microsomes was measured and was found to be similar between the two groups. The results of this study show that RVF impairs hepatic elimination of PNP and that this appears to be independent of changes in hepatic perfusion and oxygenation or alterations in hepatic content, activity, and latency of the UDP-GT.

It is unclear if reduced hepatic drug elimination in congestive heart failure is primarily due to impairment of enzyme function as a result of tissue hypoxia, to the direct effects of hepatic congestion, or to changes intrinsic to the liver, such as reductions in enzyme content and activity. We therefore compared propranolol clearance in perfused rat livers from animals with right ventricular failure (RVF) with that from control animals. Despite the fact that both groups were perfused at comparable flow rates, perfusion pressures, and levels of oxygen delivery, hepatic extraction of propranolol was significantly reduced in RVF livers (0.688 +/- 0.122 versus 0.991 +/- 0.006 ml/min/g of liver in controls, P.001). This effect was reflected in a 97% reduction in propranolol intrinsic clearance in RVF livers (5 +/- 4 versus 172 +/- 82 ml/min/g of liver in controls, P.01). In RVF livers, total hepatic CYP expression was reduced by 19% compared with controls, whereas cytochrome P450 isoenzymes 1A1/2 and 2D1 were reduced by 41 and 26%, respectively. Despite the 97% reduction in propranolol intrinsic clearance in perfused RVF liver, intrinsic clearance in microsomal preparations from the same livers was reduced by only 48% compared with controls (P.05). These findings suggest that impaired propranolol clearance in RVF is not primarily accounted for by reduced hepatic oxygen delivery or by changes in hepatic content and activity of drug-metabolizing enzymes.

Using the isolated perfused neonatal sheep liver model, we examined the disposition of propranolol (n = 8, age 0.25-10 days) and compared our findings with our previous study from the perfused near-term fetal sheep liver (Ring JA, et al. 1995. Drug Metab Dispos 23:190-196). Within 45 min of dosage, perfusate propranolol levels had fallen by three orders of magnitude to be less than the limit of detection. Perfusate disappearance curves were monoexponential in six experiments and biexponential in two experiments. The mean shunt-corrected hepatic extraction ratio was 0.92 +/- 0.09, much greater than that seen in the fetal sheep liver (0.26 +/- 0.13, P0.0001) but still less than values in the adult sheep (0.97). At the conclusion of the perfusion, 4-hydroxypropranolol was the major metabolite present and 5-hydroxypropranolol and N-desisopropylpropranolol were minor metabolites. We conclude that the isolated perfused neonatal sheep liver is a useful model with which to study the maturation of neonatal hepatic drug oxidation. Our study shows that propranolol is rapidly eliminated by the neonatal liver to form several metabolites at rates far greater than in the fetal liver, but rates of elimination have not yet reached that reported in the adult sheep liver.

We examined the metabolism of para-nitrophenol (PNP) in the isolated perfused neonatal sheep liver (n = 8, 0.25-11 days) and compared the findings with our previous data from the perfused near-term fetal sheep liver (Ring, J. A., et al. Drug Metab Dispos 1996, 24, 1378). A three-step dosage regimen was used (72, 144, and 288 micromol of PNP). At the end of each dosage phase, PNP had fallen below detectable levels, and 101 +/- 16% of the dose was accounted for as PNP conjugates. Elimination of PNP from perfusate varied with dose. Elimination was first order with the 72-micromol dose; with the 144-micromol dose, elimination was first order in four livers but Michaelis-Menten kinetics in the remaining four. With all the 288-micromol doses, elimination was Michaelis-Menten and gave the following biochemical parameters: K(m) = 255 +/- 138 microM (fetal = 14.7 microM, P0.01), V(max) = 515 +/- 285 nmol/min/g liver (fetal = 34.3 nmol/min/g liver, P0.01), and intrinsic hepatic clearance = 2.36 +/- 1.21 mL/min/g liver (fetal = 4.74 mL/min/g liver, P0. 05). The mean shunt-corrected hepatic extraction ratio of PNP was 0. 82 (range, 0.40-1.0) and strongly correlated with neonatal age (r = 0.90, P0.05). We conclude that PNP is highly extracted by the isolated perfused neonatal sheep liver at much higher efficiency than in the near-term fetal sheep, reflecting a maturation of conjugation that progresses further in the early neonatal period.

Propranolol extraction in vivo by the left lobe of the fetal sheep liver is greater than that by the right lobe, and this may be due to the fact that oxygenation of the left lobe is greater than that of the right lobe. To explore this hypothesis, we studied the elimination of (R)-(+)-propranolol (PROP) by right and left lobes of the intact isolated perfused fetal sheep liver model, in which there is equal oxygenation of both liver lobes. After isolation of the liver, near-term fetal sheep livers (n = 11) were perfused (2.68 +/- 1.05 ml/g liver/min) in situ via the umbilical vein in a 1-liter recirculating system. PROP was infused (1.2 mg/hr) into the reservoir after an initial bolus dose (2.3 mg). Perfusate samples were taken from the common and right and left hepatic veins every 10 min for determination of PROP concentrations and oxygen consumption over the 180-min experimental period. Mean ductus venosus shunt through the liver was 42 +/- 21% of perfusate flow. Oxygen consumption was not significantly different between the left and right lobes of the liver (0.79 +/- 0.46 and 0.67 +/- 0.44 micromol/g liver/min, respectively, P.05), nor was there any significant difference between lobes in PROP hepatic extraction at steady state (0.25 +/- 0.20 and 0.25 +/- 0.23, respectively, P.05). This supports the hypothesis that the difference between lobes in PROP extraction in vivo may be due to the difference in degree of oxygenation of the left and right lobes that is known to be present in vivo.

The move to develop clinical practice guidelines in Australia is gaining momentum as part of a national approach to improving the quality of clinical practice. The National Health and Medical Research Council has published a "guidelines for guidelines". While it has also produced guidelines for nine specific clinical topics, it is now passing this role to professional organisations, such as clinical colleges and learned societies, and reverting to an overseeing, facilitating and credentialling role.

We investigated the effect of acute myocardial infarction (MI) on the hepatic clearance of theophylline in rats using the coronary artery ligation model. After 48 hr of ligation, there were significant changes in left ventricular performance in the MI rats, compared with controls, as indicated by elevated left ventricular end-diastolic pressure, reduced mean arterial pressure, and reduced left ventricular systolic pressure (20 +/- 2 vs. 12 +/- 3 mm Hg, p0.01; 90 +/- 6 vs. 101 +/- 6 mm Hg, p0.01; and 100 +/- 8 vs. 114 +/- 8 mm Hg, p0.01, respectively). Despite these changes, MI rats were able to maintain their cardiac output at rest (77.9 +/- 6.8 vs. 77.2 +/- 9.2 ml/min), and there was no change in mean central venous pressure (3 +/- 1 vs. 2 +/- 1 mm Hg). Although hepatic perfusion and oxygenation were preserved (17.3 +/- 2.2 vs. 18.7 +/- 3.3 ml/min and 127 +/- 27 vs. 125 +/- 19 mumol/min respectively), clearance of theophylline was reduced by 23% in the MI rats, compared with controls (0.86 +/- 0.20 vs. 1.12 +/- 0.17 ml/min, p = 0.01). There was no significant correlation between theophylline clearance and the infarct size (r = -0.038, p0.05). These findings demonstrate that the elimination of theophylline is impaired after acute MI, independent of any changes in hepatic perfusion or oxygenation.

Using our recently described, isolated perfused fetal sheep liver model, we have studied the metabolism and disposition of para-nitrophenol (PNP) in intact fetal liver. Fetal sheep (mean gestational age, 137 +/- 7 days; range, 127-145 days; n = 8) were delivered under anesthesia near term, and the livers were isolated and perfused in situ, via the umbilical vein, in an oxygenated 1-liter recirculating system, at pH 7.40 at 37 degrees C. The perfusate delivery rate was 4.39 +/- 1.46 ml/g liver/min. Either a 14-micromol (n = 4), 72-micromol (n = 3), or 144-micromol (n = 5) bolus dose of PNP was added to the reservoir. Samples were taken from the reservoir every 5-10 min, and all bile was collected at 15-30-min intervals. Elimination of PNP from perfusate demonstrated Michaelis-Menten kinetics, and the calculated pharmacokinetic parameters for PNP elimination were KM = 13.0 +/- 9.66 microM, Vmax = 32.1 +/- 22.4 nmol/min/g liver, and intrinsic clearance = 3.39 +/- 2.54 ml/min/g liver. At the end of the 120-min perfusion period, PNP could be accounted for entirely as PNP-sulfate (PNP-S) and PNP-glucuronide (PNP-G). The perfusate ratio of PNP-S to PNP-G at 120 min was 2.21 +/- 0.88 at the 14-micromol dose, 0.86 +/- 0.56 at the 72-micromol dose, and 0.31 +/- 0.17 at the 144-micromol dose, because of saturation of sulfate production with increasing dose. PNP-S and PNP-G were eliminated into bile in small amounts (3% of dose), and the PNP-S/PNP-G ratio in bile was 1. We conclude that near-term fetal sheep liver can metabolize PNP to PNP-G and PNP-S with efficiencies that may be comparable to those of adults, that, as in adults, sulfation is of low capacity, relative to glucuronidation, and that, unlike adults, fetuses have little capacity to transport the PNP-G formed in the hepatocytes into bile.

The electrical resistivity of mammalian tissues varies widely and is correlated with physiological function. Electrical impedance tomography (EIT) can be used to probe such variations in vivo, and offers a non-invasive means of imaging the internal conductivity distribution of the human body. But the computational complexity of EIT has severe practical limitations, and previous work has been restricted to considering image reconstruction as an essentially two-dimensional problem. This simplification can limit significantly the imaging capabilities of EIT, as the electric currents used to determine the conductivity variations will not in general be confined to a two-dimensional plane. A few studies have attempted three-dimensional EIT image reconstruction, but have not yet succeeded in generating images of a quality suitable for clinical applications. Here we report the development of a three-dimensional EIT system with greatly improved imaging capabilities, which combines our 64-electrode data-collection apparatus with customized matrix inversion techniques. Our results demonstrate the practical potential of EIT for clinical applications, such as lung or brain imaging and diagnostic screening.

The effect of right heart failure on theophylline clearance was investigated in rats in which right ventricular pressure overload was produced by pulmonary artery constriction (PAC). Fifteen wk after the surgery, compared to sham-operated controls (n = 9), PAC rats (n = 9) showed markedly elevated mean central venous pressure (11 +/- 3 vs 1.44 +/- 0.88 mm Hg, P = .0001), and increased right ventricular weight (0.229 +/- 0.047 vs 0.124 +/- 0.013 g/100 g body weight, P = .0001). Centrilobular hepatic congestion was present in all PAC rats and total hepatic oxygen delivery was reduced significantly compared to controls (146 +/- 58 mumols/min vs. 206 +/- 28 mumol/min; P = .025). In the PAC group, theophylline clearance was reduced (0.82 +/- 0.12 ml/min vs. 0.96 +/- 0.13 ml/min in controls; P = .014), and there was a nonlinear correlation between theophylline clearance and total hepatic oxygen delivery (r = .82). These results suggest that in animals with PAC, metabolism of theophylline was impaired as a result of a reduction in total hepatic oxygen delivery. Therefore, in addition to the known effect of reduced hepatic blood flow on the hepatic clearance of "flow limited" drugs, reduction of hepatic oxygen delivery may be another important mechanism that can lead to reduction in hepatic clearance of capacity-limited drugs in congestive heart failure.

The effect of heart failure on the hepatic elimination of low-clearance drugs has not been clearly defined. We investigated the effect of left ventricular failure on theophylline clearance in rats. Cardiovascular function and theophylline pharmacokinetics were studied in conscious rats 6-8 weeks after left anterior descending coronary artery ligation. Rats with infarcts involving35% of the left ventricle (N = 9) had severe left ventricular failure, and, compared with control rats (N = 9), had reduced cardiac output (97.3 +/- 18.2 vs. 132 +/- 26 ml/min; p0.05), reduced mean arterial blood pressure (86 +/- 20 vs. 109 +/- 16 mm Hg; p0.05), markedly elevated left ventricular end-diastolic pressure (25.9 +/- 13.6 vs. 10.6 +/- 3.9 mm Hg; p0.01), and increased lung weight. There was also an increase in central venous pressure (6.44 +/- 2.60 vs. 3.67 +/- 2.60 mm Hg; p0.05), but no evidence of hepatic congestion, as judged by liver weights (14.7 +/- 1.5 vs. 15.3 +/- 1.3 g) and liver histology. However, total hepatic blood flow, total hepatic oxygen delivery, and theophylline clearance were found to be similar in both groups (1.66 +/- 0.30 vs. 1.75 +/- 0.38 ml/min/g liver weight; 12.4 +/- 1.8 vs. 13.3 +/- 3.7 mumol/min/g liver weight and 0.451 +/- 0.097 vs. 0.438 +/- 0.079 ml/min/100 g body weight), respectively. Taking the infarct group as a whole, total hepatic oxygen delivery was linearly correlated to theophylline clearance (r = 0.66, p0.02).(ABSTRACT TRUNCATED AT 250 WORDS)

We have used an isolated perfused fetal sheep liver preparation to study the fetal hepatic metabolism of propranolol in vitro in the intact organ. Eight livers were perfused in situ via the umbilical vein in an oxygenated recirculating system at 300 ml/min. Radiolabeled 15-microns microspheres were used to quantify the hepatic ductus venosus shunt. Propranolol (4 mg) was dosed into the reservoir as a single bolus and perfusate and bile sampled over 150 min. Propranolol, 4-hydroxy propranolol (4OHP), 5-hydroxy propranolol (5OHP), desisopropylpropranolol (DIP), naphthoxylactic acid (NLA), and alpha-naphthoxyacetic acid (NAA) were assayed by HPLC, before and after deconjugation by enzyme hydrolysis. Mean age was 125 +/- 10 days, and mean liver weight was 66.1 +/- 18.8 g. Oxygen consumption (1.10 +/- 1.03 mumol/g/min), bile flow (0.51 +/- 0.18 microliters/g/min), and perfusion pressure (8.7 +/- 3.3 mm Hg) were stable. Ductus venosus shunt was 41.6 +/- 17.4% of umbilical vein flow. Propranolol clearance was 26.2 +/- 13.4 ml/min, and shunt-corrected extraction of propranolol was 0.26 +/- 0.13. The relative amounts of metabolites in perfusate after 150 min were: 4OHP (25.1%), 5OHP (5.08%) (ring-oxidation products), DIP (6.57%), and NLA (4.33%) (side-chain oxidation products). No alpha NAA (a product of N-dealkylation of NLA) was detected. Except for NLA, metabolites were present predominantly as conjugates. Biliary excretion of unchanged drug and metabolites accounted for a further 1.33% of the propranolol dose. These data indicate that, although the hepatic clearance and extraction of propranolol are low, the fetal sheep liver can metabolize propranolol by both ring- and side-chain oxidation reactions and can conjugate these metabolites.

A planar array of electrodes has been used to provide a longitudinal section of the stomach. Impedance changes at the gastric frequency of 0.05 Hz can be detected. The changes are mainly located around the periphery of the stomach image, suggesting that they are the result of movement of the stomach wall. The generation of a vector histogram of wall movement gives a non-invasive method which appears to quantify the peristaltic waves which produce transport in the stomach.

The organic cation cimetidine undergoes renal tubular secretion in the near-term ovine fetus. We investigated the ontogeny of renal tubular secretion of organic cations in the fetus from 80 days of gestation (term = 145). Sixteen sheep were administered both cimetidine and ranitidine in random order by a combination of bolus and i.v. infusion to achieve steady-state plasma concentrations of 1000 to 2000 ng/ml. A further two sheep received cimetidine only. Steady-state plasma concentrations were reached within 2 to 3 hr. Creatinine was used as a marker of glomerular filtration rate. Maternal renal clearance of cimetidine (0.51 +/- 0.18 l/min) and ranitidine (0.54 +/- 0.14 l/min) were not correlated with the period of gestation. Cimetidine/creatinine and ranitidine/creatinine renal clearance ratios were higher than unity being 5.48 +/- 1.91 and 5.65 +/- 1.18, respectively. Fetal creatinine renal clearance increased exponentially with gestational age (r2 = 0.577, P less than .001). Fetal renal clearance of both cimetidine and ranitidine also increased exponentially with gestational age, this trend being more clear-cut for cimetidine (r2 = 0.582, P less than .001) than for ranitidine (r2 = 0.254, P = .046). The rates of increase for cimetidine and ranitidine were similar to that for creatinine (P greater than .05). At 80 days, cimetidine/creatinine and ranitidine/creatinine renal clearance ratios (3.0 and 4.4, respectively) were higher than unity and did not increase further during the remainder of gestation. Therefore, the ovine fetus possesses an efficient tubular secretory pathway for organic cations by 80 days of gestation.(ABSTRACT TRUNCATED AT 250 WORDS)

The bidirectional placental transfer of sodium [11,12-di-3H]chenodeoxycholate and sodium [14C]deoxycholate was studied in conscious pregnant sheep near term. In fetal-to-maternal studies, radiolabeled bile salt was injected into the fetal portal vein, and the daily excretion of radiolabel in maternal hepatic bile was measured over 3-4 days. In maternal-to-fetal studies, the mother received daily injections of radiolabeled bile salt, and the accumulation of label in the fetal pool was measured after 6-9 days. Bile salts were transferred predominantly as the taurine conjugate. Transfer rates were 1) fetus to mother; chenodeoxycholate, 6.7 mumol/24 h and deoxycholate, less than 0.5 mumol/24 h and deoxycholate, 1.4 mumol/24 h. We conclude that, in sheep near term, deoxycholate derived from the mother slowly accumulates in the fetus, while the placenta acts as an excretory route for fetal chenodeoxycholate.

Vasoactive intestinal polypeptide (VIP) is released into the portal circulation by a meal stimulus, but is rapidly cleared from plasma. Although it is known to bind to receptors on liver cells, the role of the liver in the clearance of VIP is not clearly defined. We therefore studied the disappearance of VIP in recirculating and in single pass isolated perfused rat liver (IPRL) preparations. Disappearance of added VIP was rapid in recirculating IPRL experiments with a half life of ca. 30 min. In single-pass steady-state studies in which livers were perfused at 16 ml/min for 30 min, clearance of VIP was complete (16 ml/min) at concentrations of 500 fmol/ml, but clearance fell to 3 and 1 ml/min at perfusate concentrations of 8 and 40 pmol/ml respectively. Further experiments to evaluate whether VIP was disappearing in perfusate itself demonstrated substantial metabolism of VIP in perfusate which had previously been circulated through a liver for 90 min. The products of metabolism were identical to those found in the IPRL. We conclude that VIP is rapidly cleared as it passes through the isolated perfused rat liver model with a significant proportion of clearance attributable to release of a peptidase from the liver into the perfusate.

The use of cimetidine administered by bolus intravenous injection to critically ill patients has been associated with serious cardiac arrhythmias, due presumably to high initial plasma concentrations. The aim of this study was to determine the range of infusion times of a single 200 mg dose of cimetidine which would avoid high initial drug concentrations while maintaining a duration of effective concentrations no less than that resulting from bolus injection. Computer simulations of both maximum plasma cimetidine concentrations and duration of effective plasma cimetidine concentrations versus duration of infusion were based on mean pharmacokinetic date from 6 peptic ulcer patients who had received cimetidine 200 mg i.v. over 5 min. The simulations indicated that to reduce maximum plasma cimetidine concentrations by at least 50%, while maintaining the duration of effective plasma concentrations, the infusion time should be at least 30 min and no longer than 4.5 h. The validity of the simulations was subsequently tested in 4 of the patients, who received cimetidine 200 mg i.v. over 30 min. The mean maximum plasma concentration for the 30 min infusion (4.57±0.53 µg/ml) was, as predicted, approximately half that corresponding to bolus administration in these patients (8.97±1.96 µg/ml). Moreover, the duration of effective concentrations for the infusion (1.43±0.28 h) was significantly greater than that for the 5 min infusion (1.21±0.31 h). We suggest that where an acute intravenous dose of cimetidine (200 mg) is indicated, it should be administered over at least 30 min rather than as a bolus.

Omeprazole, a substituted benzimidazole which suppresses gastric acid secretion, and its sulphone and sulphide metabolites were simultaneously measured in human plasma and urine using a selective, reversed-phase, high-performance liquid chromatographic method with a sensitivity of 5 ng/ml for omeprazole, 30 ng/ml for omeprazole sulphone, and 50 ng/ml for omeprazole sulphide. The coefficients of variation for within-day assays were 4.4, 7.5, and 17.5%, respectively. In a pilot pharmacokinetic study, 40 mg of omeprazole (encapsulated enteric-coated granules) were administered to two healthy volunteers. Peak plasma concentrations for omeprazole of 240 and 520 ng/ml, and for omeprazole sulphone of 320 and 400 ng/ml, were reached between 3 and 4 h post-dose. Omeprazole concentrations fell rapidly with apparent half-lives of about 40 min, and concentrations of both omeprazole and the sulphone metabolite were below the minimal detectable level by 6–8 h. Omeprazole sulphide could not be detected in this study.