The influence of duration of intravenous infusion of an acute dose on plasma concentrations of cimetidine.
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Adult↗
Biomedical subjects
D J Morgan
Publications and source records attributed to D J Morgan.
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.
Animals↗
Elimination of amphotericin B in impaired renal function.
The influence of impaired renal function on the steady-state plasma clearance of amphotericin B was determined in seven patients with creatinine clearances ranging from zero to normal. Contrary to previous reports, steady-state plasma concentrations of total drug were lower in uremic patients than in patients with normal renal function. Total plasma clearance of amphotericin B ranged from 16.7 to 39.9 ml/min, correlated directly with the plasma creatinine concentration, and correlated inversely with the creatinine clearance. Urinary excretion of unchanged drug accounted for less than 10% of the dose. In 10 healthy subjects, mean percent of amphotericin B unbound in plasma was 3.55 +/- 0.32 (SD). Binding was determined in a further group of 10 uremic patients. Mean unbound percent (4.15 +/- 0.73, SD) was higher than in the healthy subjects, and the binding ratio (molar concentration of bound to unbound drug) correlated weakly with the creatinine clearance. This suggests that plasma clearance of unbound amphotericin B and, therefore, steady-state plasma concentrations of unbound drug are not affected by renal impairment, and that dosage requirements will be overestimated if based on measurements of total drug plasma concentration.
Adult↗
Plasma binding of thiopentone in late pregnancy.
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Blood Proteins↗
Absorption of orally administered amphotericin B lozenges.
The systemic absorption of amphotericin B, administered as a 10 mg lozenge, was investigated in 14 patients with malignancies, who received three or four doses daily during chronic administration. The mean plasma amphotericin B concentration, measured 3 h after the morning dose on from 1-20 occasions over a 1-80 day period, ranged among subjects from 46 +/- 13 ng/ml (s.d., n = 20) to 136 +/- 25 ng/ml (n = 19). Using the previously reported intravenous clearance of the drug, the fraction of the dose absorbed was estimated at 8.3-9.9%. This is considerably greater than that estimated from earlier reports (0.2-0.9%), which used much higher oral doses (2-10 g/day).
Absorption↗
Plasma histamine in asthmatic and control subjects following exercise: influence of circulating basophils and different assay techniques.
Arterial plasma histamine concentrations were measured after exercise in 10 subjects with extrinsic atopic asthma, 10 who were non-atopic and non-asthmatic and seven who were atopic but non-asthmatic, by a single isotope radioenzymatic assay. Significantly higher plasma histamine concentrations were found in the asthmatic subjects before exercise than in the non-atopic controls (p less than 0.05). The mean histamine concentration rose after exercise in all groups but the increased levels were not significantly different from pre-exercise values. Similarly, mean circulating basophil counts increased in all groups after exercise, and a highly significant correlation was found between basophil counts and whole blood histamine concentrations (p less than 0.001). In vitro studies showed that there was a significant correlation between the number of basophils added to plasma samples and the concentrations of histamine subsequently detected. Although the mean concentrations of plasma histamine and whole blood histamine and number of basophils in the atopic control group were intermediate between those found in the atopic asthmatic and non-atopic controls, none of the differences was significant. Venous plasma histamine concentrations after exercise were measured in a further five subjects with extrinsic atopic asthma and five non-atopic, non-asthmatic subjects before and after exercise with the more sensitive and specific double isotope radioenzymatic assay. Concentrations of plasma histamine measured by this assay were about one tenth of those measured by the single isotope radioenzymatic assay. Although a small rise in mean plasma histamine concentration occurred in both groups after exercise there was no significant difference in these levels either between or within the groups. We find no evidence from these studies on measurement of peripheral blood histamine to support the hypothesis that mast cell mediator release is implicated in the pathogenesis of exercise induced asthma.
Adult↗
Placental transfer and renal elimination of cimetidine in maternal and fetal sheep.
The placental transfer and renal elimination of cimetidine were studied at steady state in near-term pregnant sheep. In seven nonanesthetized sheep, maternal dosage produced mean steady-state plasma concentrations of 776 +/- 217 ng/ml in the mother and 32 +/- 15 ng/ml in the fetus. Total cimetidine clearance was 41.63 +/- 9.10 liters/hr in the mother, whereas renal cimetidine clearance was 29.96 +/- 15.74 liters/hr in the mother and 1.53 +/- 0.48 liters/hr in the fetus. The mean ratio of cimetidine/creatinine renal clearance was similar in fetus and adult and was considerably greater than unity (7.5 and 7.1, respectively), suggesting active tubular secretion of equal efficiency in both. Fetal dosage in six of the nonanesthetized preparations reversed the maternal-fetal plasma cimetidine concentration gradient (fetal plasma = 16,895 +/- 5,507 ng/ml; maternal plasma = 513 +/- 184 ng/ml). At these very high fetal plasma concentrations, the mean fetal cimetidine/creatinine clearance ratio (2.1) was significantly lower, consistent with the saturation of an active renal tubular secretory process. In four anesthetized sheep, both maternal and fetal renal cimetidine clearances (9.83 +/- 5.39 and 0.32 +/- 0.14 liters/hr, respectively) were 70 to 80% lower than in nonanesthetized sheep. Umbilical venous and arterial cimetidine concentrations were similar (42 +/- 11 and 43 +/- 11 ng/ml, P greater than .05) but substantially less than the maternal plasma concentration (1535 +/- 500 ng/ml). Thus, the principal gradient occurs across the placenta rather than across the fetus. This suggests that, although the fetal kidney can extract cimetidine efficiently, low fetal drug concentrations are primarily due to the placenta and not to fetal drug elimination.
Animals↗
Use of unbound drug concentration in blood to discriminate between two models of hepatic drug elimination.
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Computers↗
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.
Animals↗
Plasma protein binding of etidocaine during pregnancy and labour.
Preliminary studies of the ultrafiltration method for measuring the extent of plasma protein binding of etidocaine showed that etidocaine binding was both pH and concentration dependent. Etidocaine (1 microgram/ml) was found to bind avidly to a physiological concentration (74 mg/dl) of alpha 1-acid glycoprotein (alpha 1-AGP) (7.23 +/- 0.64%, mean +/- SD, unbound). In vitro investigation of etidocaine binding in plasma obtained from blood bank donors and from 19 pregnant women prior to induction of labour, during early labour, mid-labour and delivery showed no difference in etidocaine binding (10.3 +/- 3.3%, 7.06 +/- 2.66%, 8.15 +/- 2.57%, 7.84 +/- 3.74% and 9.28 +/- 6.06% unbound respectively). There was a significant increase in the mean plasma total free fatty acid (FFA) concentration from pre-labour (0.535 +/- 0.240 mM) to delivery (0.948 +/- 0.28 mM), while plasma albumin and beta-lipoprotein concentrations remained constant. Alpha 1-Acid glycoprotein concentration tended to increase slightly from pre-labour to early labour (p less than 0.1) but was still within the normal physiological range. There was no correlation between etidocaine binding ratio and the concentrations of FFA or plasma proteins except for a poor correlation with the alpha 1-AGP concentration (r = 0.361, p less than 0.05). Storage of plasma and inadequate control of plasma pH during ultrafiltration appeared to give spurious binding values. These studies with the extensively bound basic drug etidocaine suggest that unlike many acidic drugs which are bound predominantly to serum albumin, the binding of alpha 1-AGP - bound basic drugs may be unaffected by pregnancy and labour.
Acetanilides↗
The effect of duration of intravenous infusion on maximum and threshold blood concentration for drugs exhibiting biexponential elimination kinetics.
The relationships among peak blood concentration (Cmax), the time (tD) during which blood concentrations are maintained above the minimum effective concentration (Cmin), and the duration of a constant-rate intravenous infusion (T) of a drug exhibiting biexponential pharmacokinetics were simulated by digital computer using Newton iterative procedures. These simulations showed that, in contrast with our previous findings for drugs with monoexponential pharmacokinetics, the relationships are more complex due to the larger number of variables. Therefore, investigation of these relationships for biexponential drugs should be done on a drug by drug basis. Accordingly, meperidine and sulfamethoxazole were chosen as examples of drugs which exhibit biexponential kinetics and were used to determine what errors were involved in using the simpler guidelines for drugs which exhibit monoexponential kinetics as an approximation. These simulations showed the following . (a) The effect of T on Cmax may be adequately estimated by using the guidelines for monoexponential kinetics with the elimination half-life (t1/2) taken as t1/2 lambda1, provided that lambda1 is 20 to 30 times lambda2 and that the AUC of the distribution phase (i.e., C1/lambda1) comprises greater than about 20% of the total AUC. (b) As with monoexponential drugs, it is possible to obtain a larger tD by infusing the dose compared to that obtained with a bolus, if the value of C(0)/Cmin less than 2.5. (c) Using th approximation of monoexponential pharmacokinetics to estimate the effect of T on tD will underestimate both tD and the maximum infusion time, which will just attain the Cmin unless the AUC of the distribution phase comprises only a very small proportion of the total AUC. (d) The simulations with meperidine also showed that the nature of the relationship between tD and T varies depending on whether Cmin is maintained in the distribution phase or in both the distribution and elimination phases.
Computers↗
A comparison of cefuroxime and co-trimoxazole in severe respiratory tract infections.
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Adult↗
Histamine, neutrophil chemotactic factor and circulating basophil levels following exercise in asthmatic and control subjects.
Significant increase in the maximum post-exercise values of plasma histamine (PH), whole blood histamine (WBH) and neutrophil chemotactic factor (NCF) occurred in arterial blood within the first hour after exercise in asthmatic patients. However, similar changes in PH and WBH also occurred in the control group. Significant increases in circulating basophil counts following exercise were found in both groups, which closely mirrored the changes in PH and NCF, and there was a highly significant correlation between rises in WBH and basophil counts (P less than 0.001). When plasma histamine as assayed in venous blood using a more sensitive and specific double isotope radio enzymatic assay no significant alteration in plasma histamine levels was detected in either the asthmatic or the control group. We conclude that there is no evidence from these studies to support the suggestion that mast cell mediator release is involved in the pathogenesis of exercise-induced asthma, and that any observed changes in levels of PH and NCF after exercise may be related to changes in levels of circulating basophils.
Adult↗
Urinary excretion of placentally transferred thiopentone by the human neonate.
The urinary excretion of thiopentone and its metabolite, pentobarbitone, was studied in 7 neonates whose mothers-had received thiopentone. During the urine collection period (range 39.3-63.8 h), a mean of 26.4 micrograms thiopentone was recovered, representing only a mean of 0.0066% of the maternal dose. This suggests that the elimination of thiopentone by the neonate occurs mainly by metabolism. The metabolite pentobarbitone could not be detected. Mean elimination half-life of thiopentone, calculated from sigma-minus plots, was 8.04 h which is similar to the value reported previously in adults. This contrasts with other barbiturates which show much longer half-lives in neonates than in adults.
Female↗
Severe peripheral neuropathy complicating legionnaires' disease.
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Adult↗
Pharmacokinetics and plasma binding of thiopental. I: Studies in surgical patients.
The pharmacokinetics and plasma protein binding of thiopental were investigated in 5 female patients who received a bolus intravenous dose of the drug for induction of anesthesia for gynecologic surgery. Blood samples were collected for 3 to 4 days after the dose. Plasma protein binding determinations were also carried out by ultrafiltration and equilibrium dialysis on samples from a panel of healthy volunteers. Plasma concentrations of thiopental were determined by reverse-phase, high-performance liquid chromatography. The coefficient of variation of the method was 2.8 per cent (n equals 10). In healthy volunteers, the plasma protein binding of thiopental was concentration dependent. Percentage bound ranged from 96.7 (n equals 4, SD equals 0.8) at 150 micrograms/ml. Therefore, saturation of binding sites on rapid administration of the drug may occur, exposing vital organs to unexpectedly high concentrations of free drug. Values of the fraction of thiopental bound in plasma obtained from the surgical patients during the hour following drug administration were similar to values obtained in healthy volunteers at comparable concentrations. Mean pharmacokinetic parameters obtained for thiopental in the surgical patients were as follows: initial distribution volume 13.81 (SD equals 9.4), apparent volume of distribution 233 1 (SD equals 98), volume of distribution at steady state 97.51 (SD equals 40), elimination half-life 11.5 h (SD equals 1.0) and systemic plasma clearance 0.150 l/min (SD equals 0.063). None of these parameters correlated with body weight. Values reported by other workers vary from ours and this variation may be explained by the much shorter duration of blood collection used in those studies.
Adult↗
Pharmacokinetics and plasma binding of thiopental. II: Studies at cesarean section.
This study was undertaken to investigate the effect of pregnancy on the disposition of thiopental and to determine the major factors which influence the placental transfer of the drug to the fetus. Maternal venous (MV) and umbilical venous (UV) and arterial (UA) blood samples were collected at delivery from 11 pregnant women at term who received thiopental for induction of anesthesia for elective cesarian section. A detailed study of the pharmacokinetics of thiopental was carried out in 7 of these subjects and blood samples were collected for 80 to 100 hours following thiopental administration. A transient rise in thiopental plasma concentration was observed at delivery. Mean values of pharmacokinetic parameters (plus or minus SD) were: initial distribution volume (V1) 17.31 (plus or minus 8.5), apparent volume of distribution (Vdbeta) 564 1 (plus or minus 343), volume of distribution at steady state (Vss) 2881 (plus or minus 180), systemic plasma clearance (Clp) 0.286 l/min (plus or minus 0.156), rate of change of volume of distribution at zero time (RVd0) 1.03 l/min (plus or minus 0.36) and elimination half-life (t1/2) 26.1 h (plus or minus 12.6). Comparison of these data with our previously reported data in nonpregnant surgical patients shows that Vdbeta, Vss, T1/2 are significantly greater at cesarian section (P less than 0.05) and that systemic plasma clearance shows a similar trend. UA and UV values at delivery were similar within individuals. There was no correlation between the ratio UV/MV at delivery and the dosing-delivery interval (delta t), or between UV and the administered dose or delta t. There were good correlations between UV (corrected for dose) and the reciprocals of V1, Vdbeta, Vss, and plasma clearance of thiopental. This demonstrates that differences in maternal distribution and elimination characteristics of thiopental may be more important determinants of intersubject differences in fetal drug exposure than differences in dose or delta t.
Adult↗
Fetal hepatic function: the disposition of propranolol in the pregnant sheep.
The placental transfer, and maternal and fetal disposition, of the beta-adrenoreceptor blocking drug propranolol were studied in the pregnant sheep near term. In separate studies, propranolol (1 mg/kg) was administered peripherally or into the portal vein as an i.v. bolus, to either mother or fetus. Both mother and fetus were provided with vascular and bile duct cannulae, enabling plasma concentrations and biliary excretion of the drug to be measured over 6 hours. Placental transfer of propranolol was rapid and bidirectional. Comparison of the systemic blood levels obtained after peripheral and portal dosage indicated that hepatic extraction was much more efficient in the adult. This was supported by an apparent/true biliary clearance ratio of approximately 20 in the adult, and only 2-3 in the fetus. These studies show that the fetus near term is exposed to propranolol administered to the mother at a time when its ability to clear the drug is not fully developed.
Animals↗