Physiological basis of multicompartmental models of drug distribution.

Although most pharmacokinetic studies are conducted in normal subjects, their clinical utility depends on the reliability with which the results can be extrapolated to patients. This reliability can be improved by increased understanding of how drug absorption and disposition mechanisms are affected by physiological changes or by disease. In recent years, important insight has been gained regarding the effects of altered renal function on drug elimination by the kidneys. There has also been considerable progress in defining the interaction of hemodynamic and metabolic factors that affect the hepatic elimination of drugs. Although comparatively little progress has been made in elucidating the underlying basis of changes in the rate and extent of drug distribution, Arthur Atkinson and colleagues analyse methods of compartmental pharmacokinetic analysis that may provide physiological insight into the factors affecting drug distribution.

Characterization of theophylline binding to serum proteins in pregnant and nonpregnant women.

Sera from 10 subjects in the third trimester of pregnancy and from 10 nonpregnant women were studied to elucidate the mechanism underlying decreased theophylline protein binding during pregnancy. Consistent with the physiologic hypoalbuminemia of pregnancy, serum albumin concentrations averaged only 3.2 +/- 0.3 gm/dl (+/- SD) in pregnant subjects, compared with 4.4 +/- 0.3 gm/dl in control subjects (p less than 1 x 10(-6], and this was the main cause of decreased theophylline binding. Saturation binding studies indicated a single class of theophylline binding sites. Theophylline binding capacity (N) was greater in pregnant (N = 4.3 +/- 1.0) than in nonpregnant (N = 3.3 +/- 0.4) subjects, but binding affinity (ka) averaged only 227 +/- 69 (mol/L)-1 in pregnant subjects, compared with 303 +/- 44 (mol/L)-1 in control subjects (F2,17 = 4.26; p = 0.032). At a theophylline plasma concentration of 10 micrograms/ml, the combined effects of hypoalbuminemia and lowered ka would reduce theophylline binding to 31% +/- 3% in pregnant women, compared to 39% +/- 3% in nonpregnant control subjects (p less than 1 x 10(-5]. Nonesterified fatty acid concentrations were similar in both subject groups and did not contribute to the pregnancy-associated decrease in theophylline binding.

Pharmacokinetics of prednisolone transfer to breast milk.

Prednisolone transfer to breast milk was studied in three nursing women who required oral steroid therapy for asthma. Each patient received a 50 mg intravenous dose of prednisolone phosphate, and blood and breast milk were sampled for 6 hours. Concentrations of prednisolone in milk declined more rapidly than in serum but were similar to expected unbound serum concentrations, suggesting that exchange between unbound prednisolone in serum and breast milk is relatively rapid and bidirectional. Because an average of 0.025% (range, 0.010% to 0.049%) of the prednisolone dose was recovered in milk, prednisolone transfer to breast milk does not appear to pose a clinically significant risk to nursing infants.

Theophylline pharmacokinetics in pregnancy.

Theophylline pharmacokinetics were studied serially in five women during and after pregnancy. Theophylline protein binding was reduced to 11.1% +/- 4.7% (P less than 0.01) and 13.0% +/- 5.9% (P less than 0.01) during the second and third trimesters of pregnancy, respectively, compared with 28.1% +/- 2.8% when the patients were more than 6 months postpartum. Similar comparisons indicate that theophylline distribution volume and elimination t1/2 were increased from 30.7 +/- 4.4 L and 262 +/- 57 minutes to 36.8 +/- 4.2 L (P less than 0.05) and 389 +/- 73 minutes (P less than 0.01) in the third trimester of pregnancy. In the second and third trimesters, intrinsic nonrenal clearance was reduced to 0.82 +/- 0.25 ml/min X kg (P less than 0.05) and 0.67 +/- 0.18 ml/min X kg (P less than 0.01) compared with a remote postpartum value of 1.25 +/- 0.37 ml/min X kg. However, these reductions were offset by increases in theophylline intrinsic renal clearance so that apparent reductions in the overall unbound clearance of this drug did not reach statistical significance either during pregnancy or in the early postpartum period.

Kinetics of epsilon-aminocaproic acid distribution, elimination, and antifibrinolytic effects in normal subjects.

The kinetics of epsilon-aminocaproic acid (EACA) distribution and elimination were studied in six normal subjects after a single 10-gm iv dose. Steady-state distribution volume averaged 30.01 or 0.39 l/kg. Mean elimination t 1/2 was 294 min and the elimination clearance was 0.19 l/min. Renal excretion of unchanged EACA accounted for 68% of its elimination and renal EACA clearance averaged 115% of creatinine clearance. EACA antifibrinolytic effect kinetics were also characterized in five of the subjects by the monitoring of clot lysis times in whole blood and platelet-rich plasma. Peak antifibrinolytic effects were observed 15 to 60 min after peak EACA plasma concentrations were attained. A model of maximal fibrinolysis inhibition (Emax) was used to estimate a half-maximal inhibition (IC50) of 63 +/- 19.7 microgram/ml. This agrees with the value of 0.55 mM or 72 microgram/ml that has been reported for the dissociation constant of the EACA-plasminogen complex and is consistent with the proposed biochemical mechanism of EACA action.

Simultaneous analysis of inulin and 15N2-urea kinetics in humans.

To elucidate the physiologic basis of multicompartmental systems used to model drug distribution, we studied inulin and 15N2-urea kinetics after simultaneous intravenous injection in five normal subjects. Distribution of both compounds was characterized by three-compartment models in which the central compartment corresponded to intravascular space. The mean distribution volumes of 0.164 +/- 0.009 L/kg (+/- SD) for inulin and of 0.670 +/- 0.143 L/kg for urea were similar to expected values for extracellular space and total body water, respectively. Distribution from intravascular space was kinetically heterogeneous, presumably reflecting differences in vascular beds supplied by either fenestrated and discontinuous capillaries or capillaries with a continuous basement membrane. Intercompartmental clearances of inulin and urea and the ratio of their free water diffusion coefficients were used to estimate blood flows and permeability coefficient-surface area products for the peripheral compartments. The sum of compartmental blood flows averaged 5.39 +/- 0.49 L/min and was similar to dual-beam Doppler measurements of cardiac output (5.47 +/- 0.40 L/min).

Effects of dietary protein on theophylline pharmacokinetics and caffeine and aminopyrine breath tests.

The effects of low- and high-protein diets on theophylline kinetics and the time course of changes in 13C-labeled caffeine and aminopyrine CO2 breath tests were examined in six young men. With a low-protein diet, mean theophylline clearance fell 21% (P less than 0.04) and the t1/2 rose from 8.0 to 10.6 hours (P less than 0.02). With a high-protein diet, mean theophylline clearance rose 26% (P less than 0.004) and the t1/2 shortened to 7.4 hours (P less than 0.03). Theophylline volume of distribution and protein binding did not change. Renal clearance of theophylline was lowered during the low-protein diet. Theophylline clearance correlated with caffeine breath test values during the low- (r = 0.73) and high- (r = 0.70) protein diets. Theophylline clearance correlated less well with the aminopyrine breath test values during the low- (r = 0.47) and high- (r = 0.55) protein diets. Thus dietary protein significantly influenced theophylline clearance, but the caffeine and aminopyrine breath tests showed a differential response to this important environmental factor.

A comparison of once-daily and 8-hour gentamicin dosing in the treatment of postpartum endometritis.

OBJECTIVE: To evaluate whether once-daily gentamicin dosing is as effective as the traditional 8-hour regimen for the treatment of postpartum endometritis. METHODS: Postpartum women with endometritis were randomized to receive gentamicin 5 mg/kg as a single daily dose or 1.75 mg/kg every 8 hours. All subjects also received clindamycin. Each participant had a peak serum gentamicin level of at least 5.0 micrograms/mL within the first 24 hours. The dosing regimens were compared by analyzing the number of hours that patients were febrile, the length of hospital stay, occurrence of complications, pharmacy costs, and nursing time required to administer the regimens. RESULTS: The study group (n = 62) and the control group (n = 65) were similar in demographic characteristics and the presence of endometritis risk factors. No differences were found between the groups in the number of patients who completed therapy without complications, required changes in antibiotics, or required readmission for endometritis. The groups did not differ in the number of hours that patients remained febrile after the start of therapy or in the length of hospital stay. No patient in the study group had an initial peak serum concentration less than 5.0 micrograms/mL, whereas 24 patients in the control group had initial peak serum concentrations less than 5.0 micrograms/mL and required dose adjustment, a statistically significant difference (P < .001). Pharmacy costs averaged $16.12 +/- 5.68 for the study group and $41.75 +/- 17.41 for the control group, also a significant difference (P < .001). Nurse tasking time averaged 13.62 +/- 2.56 minutes for the study group and 28.06 +/- 8.77 minutes for the control group (P < .001). CONCLUSION: In patients with postpartum endometritis, once-daily gentamicin dosing provides consistently high peak serum levels of gentamicin, requires less nurse tasking time, costs less, and is as effective as the 8-hour dosing regimen.

A randomized study of 12-mm and 15.9 mm cannulas in midtrimester abortion by laminaria and vacuum curettage.

We evaluated the adequacy of a new large-bore vacuum cannula system for midtrimester abortion by randomly allocating patients to be treated with a standard 12-mm vacuum system or the new 15.9-mm system. Cervical dilataion was accomplished by overnight placement of laminaria tents. Blood loss was similar for the two treatment groups and was significantly greater at gestational ages 17 to 18 weeks than for abortions at 16 weeks or less. Operating time was slightly less in the large-cannula group. When the 12-mm cannula was used beyond 13 weeks' gestation, forceps were usually needed to empty the uterus completely. The large-cannula system was able to empty the uterus through 16 weeks, but at 17 and 18 weeks it offered no advantage over the smaller system and forceps were always needed. Complications were minimal. We caution against forcible cervical dilatation to 16 mm and urge the use of laminaria instead. Our findings, together with published reports of the safety of late dilatations and evacuation, would appear to justify wider clinical trials by experienced investigators.

Physiologic changes in pregnancy and their effect on drug disposition.

Changes in maternal physiology occur normally during pregnancy and have the potential to alter the absorption, distribution, and elimination of drugs used therapeutically in pregnant women. These physiologic changes include: plasma volume expansion and increases in extracellular fluid space and total body water; decreased plasma albumin concentration; a compensated respiratory alkalosis; increased cardiac output with regional blood flow changes; increased renal blood flow associated with increased glomerular filtration; changes in hepatic drug metabolizing enzymes; and changes in gastrointestinal function. These changes begin in early gestation but are most pronounced in the third trimester of pregnancy. Further maternal physiologic changes occur intrapartum with some normalizing themselves within 24 hours of delivery, while others are sustained only returning to normal some 12 weeks postpartum. These physiologic changes form the basis for the need for pharmacokinetic studies during pregnancy.

Metabolism and pharmacokinetics of progesterone in the cynomolgus monkey (Macaca fascicularis).

[4-14C]Progesterone was administered to two cycling female monkeys during the luteal phase of the cycle, and blood and urine were sampled over a 24 h period. Progesterone had a volume of distribution of 1.75 +/- 0.3 L/kg, and a plasma elimination clearance of 0.06 +/- 0.03 L/kg/min. In comparison to the human, plasma progesterone binding was greater and progesterone clearance was slower in the cynomolgus monkey. The major unconjugated metabolite in plasma was 20 alpha-hydroxy-4-pregnen-3-one. In urine 6.2% of 14C-steroids were unconjugated, 2.3% of which were [14C]progesterone. Thin-layer chromatography (TLC) of conjugated metabolites in urine revealed that 24% had the mobility of sulfates, 19% that of glucuronides, and 52% were more polar. After hydrolysis of conjugates, a major fraction chromatographed with pregnanediol. However, despite evidence for the presence of a 20 alpha-hydroxyl group, none of the pregnanediol isomers could be identified among these 14C-steroids. Nevertheless, over 80% of urinary metabolites had sufficient analogy to pregnanediol to bind to an antiserum specific for ring D and the C-17 side-chain of pregnanediol.

An elevated maternal serum alpha-fetoprotein leading to the diagnosis of an immature teratoma.

A case report is presented of a woman with a maternal serum alpha-fetoprotein 17.46 multiples of the median (MOM), who was found to have an ovarian immature teratoma. It is suggested that patients who present with a maternal serum alpha-fetoprotein value greater than 9 multiples of the median receive a more comprehensive evaluation remembering that the alpha-fetoprotein in the adult can be a tumor marker.

Depot medroxyprogesterone acetate contraception in women with medical problems.

Since few clinical trials of contraceptive agents are conducted on women with medical problems, use of these agents in these populations is often based more upon theoretical considerations than clinical data. Clinicians must distinguish the risk of estrogen in the combined oral contraceptive from the risk of the progestin-only contraceptive methods. This review compares the risks of pregnancy with the risks of contraceptive methods for patients with chronic hypertension, cardiac disease, thrombotic disorders, diabetes, epilepsy, lupus erythematosus and other medical disorders. For women with certain medical problems, estrogen, but not progestogen, may be contraindicated. For these women, a long-acting progestogen, such as depot medroxyprogesterone acetate (DMPA), may offer distinct advantages.

PIP: The contraceptive implant depot medroxyprogesterone acetate (DMPA) may offer advantages to women with medical problems which contraindicate the use of estrogen. In such women, the risks of pregnancy must be weighted against the risk posed by a contraceptive method. While young women with well-controlled hypertension can use DMPA or the combined oral contraceptive, patients with uncontrolled hypertension or other risk factors may be better managed with DMPA. DMPA is also an appropriate choice for many women with cardiac disorders which can be associated with an extremely high risk of adverse pregnancy outcomes. Because it is not associated with increased thrombotic risk, DMPA is also safe in women over 35 years old who smoke. The contraceptive is likewise indicated in women with a history of thromboembolic disease (despite package labeling which was based on trials of high doses of DMPA as a cancer treatment). DMPA also is safe in women with sickle cell disease and actually has been shown to reduce the incidence of sickle cell crisis. Evidence also suggests that DMPA injections in anticoagulated women do not increase the incidence of hematoma formation. DMPA will not protect women with underlying predisposing causes of thrombosis from experiencing a thrombotic event. Whereas the contraceptive efficacy of hormonal contraception may be reduced in epileptic women using hepatic enzyme induction agents, DMPA has been reported to reduce seizure frequency with few contraceptive failures in such women. In diabetic women with peripheral vascular disease and in women with systemic lupus erythematosus, DMPA, unlike contraceptives with estrogen, avoids the enhanced risk of thrombosis. Because the best pregnancy outcome in women with medical problems occurs when the pregnancy is planned, such women should use the most effective contraceptive methods available to them.

A needed information source.

Most sources of information regarding drugs in pregnancy include information on whether a drug causes congenital anomalies and whether a drug causes changes in fetal function or neonatal adaptation. Therapeutic issues related to the treatment of maternal disease are not readily available. Despite known physiologic changes of pregnancy, drug dosages are widely assumed to be the same as the healthy adult. An informational source is needed which addresses the therapeutic issues of pregnant women.

A randomized trial of misoprostol versus extra-amniotic sodium chloride infusion with oxytocin for induction of labor.

OBJECTIVE: Our purpose was to compare the efficacy and safety of misoprostol and extra-amniotic sodium chloride infusion with oxytocin for induction of labor. STUDY DESIGN: This randomized trial compared two methods of labor induction in women requiring cervical ripening. One hundred twenty-three women undergoing labor induction with a Bishop score < or =5 were randomly selected to receive either misoprostol, 50 microg intravaginally every 4 hours, or extra-amniotic sodium chloride infusion. The primary outcome variable was the time interval from induction to vaginal delivery. RESULTS: Sixty-one women received extra-amniotic sodium chloride infusion and 62 women received misoprostol. The mean time interval from the start of induction to vaginal delivery was 15.0 +/- 5.0 hours and 16.5 +/- 7.2 hours for the extra-amniotic infusion and misoprostol groups, respectively (P, not significant). The cesarean delivery rate was not significantly different between the 2 groups (32.8% for the extra-amniotic infusion group; 19.4% for the misoprostol group). Maternal and neonatal outcomes were similar between the 2 groups. CONCLUSIONS: Both methods of induction are equally efficacious and result in similar maternal and neonatal outcomes.

Fetal reduction: is this the appropriate answer to multiple gestation?

PIP: Fetal reduction techniques, experiences at Northwestern University of Evanston, Illinois, USA, and ethical issues are discussed. The use of fetal reduction pertains to higher order multiple pregnancies due to successful fertility treatments. The risk associated with multifetal pregnancy is preterm delivery i.e., 29-31 weeks for quadruplets. In addition, survivors often have a high risk of congenital abnormalities and complications related to prematurity. 1978 marked the 1st time selective termination was possible. Other terms include "selective" birth, reduction, feticide, abortion, and multiple pregnancy reduction. The procedure takes place in the 1st or 2nd trimester, and procedures are similar to an elective abortion but with different techniques. Although there are many techniques, the preferred one is transabdominal cardiac puncture and injection of potassium chloride. A highly skilled ultrasonographer is essential for a successful technique. The complexity of the technique is one where the physician from a 2-dimensional screen must envision a 3-dimensional picture of the uterus and contents. Accurate needle placement is important. The reports from 7 clinical trials using the intracardiac potassium chloride technique are presented. The Northwestern experience includes 25 reductions between 1987-91 using fentanyl and midazolidocaine analgesia and general anesthesia with 1% lidocaine. Gestational age ranged from 9 to 13 weeks. There was total loss in 2 cases and deliveries in 8 cases including neonatal death of a very preterm set of twins. At or = 37 weeks, there were 11 pregnancies. 11 patients were or = 35 years, and 4 of the 20 30 years. In 33% of cases, only 1 pregnancy was left, which is dissimilar to other studies. Many difficulties may be faced with a complete pregnancy loss where there is a lack of support for the decision for fetal reduction. 2 concerns are mentioned in the ethical debate: the adequacy of counseling and the criteria for determining how many reductions per pregnancy. Difficulties arise in physician counseling when patients are unable to assimilate complex and detailed information, and physicians may not accurately convey information. Institutions may bias patient counseling. When an abnormality exists, the decision is easy; but with multiple normal development, the recommendation is twins. The Northwestern recommendation involves patient and family decisions and joint discussion of risk. The likelihood of severely premature delivery and maternal morbidity should also be considered, as well as the medical cost incurred with delivery and care of preterm multiple infants i.e., 1.2 million dollars for delivery of quads at 27 weeks. Science should be directed to reducing multiple pregnancies by refining technique and using fetal reduction as an interim technique. Fetal reduction is not appropriate for all multiple pregnancies.^ieng

Placenta previa: a 22-year analysis.

OBJECTIVE: Our purpose was to identify what anesthetic method is safer for women with a placenta previa. STUDY DESIGN: We retrospectively reviewed all women with placenta previa who underwent cesarean delivery during the period January 1, 1976-December 31, 1997 at Northwestern Memorial Hospital. RESULTS: Of 93,384 deliveries, placenta previa was found in 514 women. Identifiable trends with time included an increasing incidence of placenta previa (r = 0.54, P <.01); cesarean hysterectomy (r = 0.54, P <.01); placenta accreta (r = 0.45, P <.03); and regional anesthesia (r = 0.84, P <.0001). The mean gestational age at delivery was 35.3 +/- 3.4 weeks and did not change with time. General anesthesia was used for delivery in 380 women and regional anesthesia was used for 134 women. Prior cesarean delivery and general anesthesia were independent predictors of the need for blood transfusion, but only prior cesarean delivery was a predictor of the need for hysterectomy. General anesthesia increased the estimated blood loss, was associated with a lower postoperative hemoglobin concentration, and increased the need for blood transfusion. Elective and emergent deliveries did not differ in estimated blood loss, in postoperative hemoglobin concentrations, or in the incidence of intraoperative and anesthesia complications. Regional and general anesthesia did not differ in the incidence of intraoperative and anesthesia complications. CONCLUSIONS: In women with placenta previa, general anesthesia increased intraoperative blood loss and the need for blood transfusion. Regional anesthesia appears to be a safe alternative.

Single-dose methotrexate for the treatment of ectopic pregnancy: Northwestern Memorial Hospital three-year experience.

OBJECTIVE: Our purpose was to evaluate the effectiveness of single-dose intramuscular methotrexate in the treatment of ectopic pregnancies by physicians in the Department of Obstetrics and Gynecology of Northwestern Memorial Hospital and to compare the results with those of previously published studies. STUDY DESIGN: A retrospective chart review was performed of 50 patients with ectopic pregnancies treated with single-dose methotrexate according to the protocol of Stovall et al. from January 1992 to February 1995. RESULTS: The mean pretreatment level of beta-human chorionic gonadotropin was 1896.4 +/- 2399 mlU/ml. Only 32 women (64%) were successfully treated with a single dose of methotrexate. An additional 7 women required a second or third injection. The combined success rate for medical management of ectopic pregnancy with one to three doses of methotrexate was 78% (39 women). Pretreatment beta-human chorionic gonadotropin levels were significantly lower in women who responded to single-dose therapy than in those who required either two or three doses or who had failure of medical management (p = 0.0011). The mean time to resolution of beta-human chorionic gonadotropin was 26.5 +/- 17 days. Higher pretreatment levels correlated with longer resolution time (r = 0.83, p < 0.001). Eleven women (22%) with failure of medical management required surgery. CONCLUSIONS: In our series single-dose methotrexate was only 64% successful. Women with a pretreatment beta-human chorionic gonadotropin level >5000 mlU/ml had a greater probability of requiring either surgical intervention or multiple doses of methotrexate. The potential for emergency surgery remains an important risk.

Asthma and pregnancy: responsibility of physicians and patients.

The successful management of asthma during pregnancy requires a cooperative approach between the obstetrician, the physician managing the asthma, and the patient. This is emphasized by a case report describing a patient with uncontrolled asthma subsequently managed with appropriate medical and obstetrical care. Concern for maternal and fetal health and reassurance of patients are primary concerns. Guidelines for physicians and patients are outlined as are the safety of drugs and therapy in pregnant patients. Physicians must have knowledge of appropriate use of medications during pregnancy.

Heterogeneity of interstitial fluid space demonstrated by simultaneous kinetic analysis of the distribution and elimination of inulin and gallamine.

The kinetics of inulin and gallamine were studied after simultaneous i.v. injection in anesthetized dogs. The distribution of both compounds in extracellular fluid space was characterized by a three-compartment model in which the mean central compartment blood volume of 1.37 liters was identical with the expected value. The two peripheral compartments of the model appear to represent rapid and slow equilibrating interstitial fluid compartments. A mammillary model structure was selected in which intercompartmental clearance corresponds to transcapillary exchange. Previous studies indicate that inulin and smaller hydrophyllic molecules diffuse across capillary walls at rates proportional to their respective free water diffusion coefficients. For the ratio of the transcapillary permeability coefficients of inulin and gallamine to equal their free water diffusion coefficient ratio of 5.34 +/- 0.02 (+/- S.D)., it appears that the sum of blood flow to the fast and slow interstitial fluid compartments is less than cardiac output. When this assumption is made, blood flow to fast equilibrating interstitial fluid is estimated to be 39% of cardiac output, in agreement with previous measurements of splanchnic blood flow. This supports the hypothesis that the fast equilibrating interstitial fluid space is supplied by porous splanchnic capillaries that lack a continuous investment of basement membrane.