Bioavailability of trivalent iron in oral iron preparations. Therapeutic efficacy and iron absorption from simple ferric compounds and high- or low-molecular weight ferric hydroxide-carbohydrate complexes.

All available results from critical hemoglobin regeneration tests, postabsorption serum iron concentration studies, 59Fe erythrocyte incorporation and 59Fe whole-body retention measurements demonstrate that humans do absorb ferrous iron between 4 and 10 times (in the average about 5 times) better than ferric iron from therapeutic oral 50--250 mg iron doses. Ferrous sulfate iron is 3 to 4 times better available than the iron from ferric ammonium citrate or sulfate. Whereas 100 mg of ferrous sulfate iron/day are sufficient for an optimal oral compensation iron therapy and to produce initial hemoglobin regeneration rates of about 0.26 g/100 ml/day, 400 to 1000 mg of ferric iron/day are necessary for the same therapeutic effect because of the poor bioavailability of ferric iron. The ratio of the dose-absorption relationships for ferric and ferrous 59Fe was shown to decrease from 0.43 for a diagnostic 0.56 mg Fe dose to 0.21 for the therapeutic 50 mg Fe dose in subjects with normal iron stores. Absorption ratios of 0.65 for the 0.56 mg Fe dose and 0.26 for the 50 mg Fe dose were measured in subjects with depleted iron stores. At all dose levels the superior bioavailability of ferrous iron was demonstrable. A high-molecular weight ferric hydroxide-carbohydrate complex (MW similar to 30 000) was palatable but so poorly absorbed that is was practically without effect on hemoglobin regeneration even at a daily 300 mg Fe dose. Following several warnings such a useless commerecial oral iron preparation was finally withdrawn from the market. The iron from any high-molecular weight carbohydrate complex of ferric hydroxide has to be suspected to be poorly absorbed and therefore therapeutical useless, unless the opposite has been demonstrated with a reliable bioassay (59Fe absorption whole-body retention and hemoglobin regeneration test). A low-molecular weight so-called ferric hydroxide-fructose complex was shown to contain iron of more or less the same poor bioavailability as contained in ferric chloride since the iron from ferrous sulfate was about 5 times better absorable. The good absorption of ferrous sulfate iron was not further augmented by even very large oral doses of fructose since this carbohydrate did not improve the ferrous iron absorption at a fructose: Fe molar ratio of 106:1. Trivalent iron in simple compounds like ferric ammonium citrate or in low- and high-molecular weight carbohydrate complexes of ferric hydroxide is so poorly available for intestinal iron absorption in man that it cannot be used for a fast and reliable oral iron therapy with reasonably low doses as it can be easily practised with quick-lease preparations of ferrous sulfate at a 100 mg Fe2     

Metabolisches Verhalten von kolloidalem Ferrihexacyanoferrat(II)

Summary Intestinal absorption, distribution, and excretion of ferrihexacyanoferrate(II), labeled by⁵⁹Fe at the Fe(III)- and Fe(II)-atoms, respectively, was studied in rats. Following i.v. injection, the compound is separated at 60% into Fe³⁺ and [Fe(CN)₆]^4–, the residual fraction being retained by the reticuloendothelial system. [Fe(CN)₆]^4– is excreted rapidly and virtually completely by the kidneys. With oral administration the disintegration amounts to 7%, and 2% of [Fe(CN)₆]^4– is absorbed from the gut. No evidence was obtained for decomposition of [Fe(CN)₆]^4–. No toxic side-effects were observed after chronic administration of ferrihexacyanoferrate(II).

     

Effect of Amorphous Nanoparticle Size on Bioavailability of Anacetrapib in Dogs

Amorphous solid dispersions (ASDs) are used as bioavailability-enhancing formulations on the premise of the increased solubility of the amorphous form over its crystalline counterpart. Recent studies have shown that ASDs can, during dissolution, generate amorphous nanoparticles that were initially postulated to serve as a source of rapidly dissolving compound during absorption. Researchers have proposed that nanoparticles, including crystalline nanoparticles, may provide additional benefits to absorption such as drifting in the mucous layer. However, there are limited published data on the impact of nanoparticle size on bioavailability in vivo and, to our knowledge, there have been no published examples looking at the impact of differential size of in situ–generated nanoparticles from an ASD. Anacetrapib, a highly lipophilic, Biopharmaceutics Classification System IV compound, formulated as an ASD that generates nanoparticles on dissolution, was used in the studies described in this article. A differential response in bioavailability was observed with ∼100 nm or smaller particles, resulting in higher average exposure compared to ∼200 nm or larger particles. This increase in bioavailability could not be fully accounted for by the improvement in dissolution rate and was not as pronounced as that achieved by improving solubilization by coadministration with a high-fat meal.     

枸橼酸铋锌钠在狗体内药代动力学及其生物利用度

用原子吸收法测定枸橼酸铋锌钠中铋在狗体内药代动力学，铋呈现二室动力学模型．其药物动力学参数，静脉给铋０．５３３ｍｇ／ｋｇ，Ｔ１／２β为３．５６ｈ，ＡＵＣ为３．７８（μｍｏｌ／Ｌ）·ｈ．灌胃给铋６．６６，１３．３３和２０．０ｍｇ／ｋｇ三个剂量，Ｔ１／２β分别为３１．５８，３１．４２和３４．０８ｈ；ＡＵＣ为４．１２，４．９３和６．５１（μｍｏｌ／Ｌ）·ｈ；Ｔｐ为３．４６，２．３６和１．９８ｈ；Ｃｍａｘ为０．１０，０．２４和０．３３μｍｏｌ／Ｌ．用静脉注射和灌胃的中剂量ＡＵＣ统计铋的生物利用度为５．２２％．结果提示，铋胃肠吸收极少，生物利用度低，大部分从胃肠道排出体外．     

Different modes of synergistic toxicities between metam/copper (II) and metam/zinc (II) in HepG2 cells: apoptosis vs. necrosis

Both metam sodium and copper/zinc‐containing compounds are widely used as fungicides. They therefore may co‐occur in the biosphere. Despite certain studies of individual toxicity for either metam or copper (II)/zinc (II), their synergistic toxicity has not been examined. In this paper, a remarkable synergistic toxicity was observed in HepG2 cells when metam and copper (II)/zinc (II) at non‐toxic and sub‐toxic levels were combined. Unexpectedly, cell death modes between metam/copper (II) and metam/zinc (II) were different: For metam/copper (II), apoptosis was evident from morphological characteristics including cytoplasm‐chromatin condensation, phosphatidylserine (PS) exposure, SubG₀/G₁ DNA fragmentation, mitochondrial membrane potential decrease, pro/anti‐apoptotic protein activation, and cytochrome c release; for metam/zinc (II), necrosis was evident from organelle swelling and uncontrolled collapse. To our knowledge, this work first not only demonstrates the synergistic toxicities of metam and both copper (II)/zinc (II), but also verifies the different modes of apoptosis/necrosis between metam/copper (II) and metam/zinc (II). © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1964–1973, 2016.     

Bioavailability of potassium from controlled-release tablets with and without water loading

Summary The relative availability of potassium from a controlled-release multiple-units tablet (Kalinorm) and a single-unit tablet (Slow-K) were compared in 13 volunteers on a low potassium diet (less than 30 mmol), by observing changes in urinary potassium excretion after administration of a single dose of 32 mmol potassium, either with or without water loading. Irrespective of procedure, the two products had the same extent of availability. The use of water loading, and special precautions about the level of dietary potassium and its composition when studying urinary potassium excretion, are discussed. It is suggested that water loading should be avoided when investigating the rate of potassium excretion.     

Determination of cis-diamminedichloroplatinum (II) in plasma proteins and hemoglobin of cancer patients

A study was conducted to determine the levels of cis-diamminedichloroplatinum (II) (cisplatin) in plasma proteins and hemoglobin of cancer patients after cisplatin chemotherapy. Thirty-seven cancer patients with different type of cancers (lung, esophageal, urinary tract, and testicular cancer, melanoma, osteosarcoma etc) received cisplatin 32–110 mg/m² either as a single intravenous infusion or as infusions given on 5 consecutive days. Blood samples were classified according to time from previous cisplatin infusion. They included a total of 103 samples taken before the cisplatin infusion, immediately after infusion, 1, 2 or 3–5 days after infusion or 2–3, 4, or 5–7 weeks after infusion. Platinum (Pt) concentration in plasma proteins and hemoglobin was measured by atomic absorption spectroscopy (AAS). The data showed a correlation between the dose of cisplatin and the concentrations of Pt in plasma proteins and hemoglobin of cancer patients. Plasma proteins bound more cisplatin than hemoglobin, the respective maxima in the patients receiving > 50 mg/m² being 27.7 and 1.6 ng/mg protein in samples drawn immediately after treatment. The kinetics of disappearance of Pt from plasma proteins showed several components; the initial half-life was about 5–7 days. The disappearance of Pt from hemoglobin showed a single component of a half-life of 12–14 days.     

Bioavailability of metronidazole from sugar-coated tablets in humans. II. Evaluation of beagle dogs as an animal model

The bioavailability of metronidazole from five sugar-coated tablets exhibiting different dissolution behaviors relative to pH was determined in beagle dogs, and compared with that in humans administered the same preparations. The gastric pH of beagle dogs, which was determined after collecting the gastric fluid through a catheter inserted into the stomach, ranged in pH from 1.8 to 7.8. From statistical analysis of C_max and AUC_0–24, it was concluded that gastric acidity definitely affects the bioavailability of metronidazole from sugar-coated tablets. The relative values of C_max and AUC_0–24, compared with those of the tablet exhibiting the highest values, ranked similarly between corresponding gastric acidity groups of beagle dogs and humans. A significant correlation was shown between AUC_0–24 for beagle dogs and humans having low gastric acidity (P < 0.05). These results suggest the possibility that beagle dogs may be used as an animal model for testing the bioavailability of a drug preparation showing gastric acidity-dependent bioavailability in humans.     

Bioavailability studies on para-aminosalicylic acid and its various salts in man. I. Absorption from solution and suspension

The relative bioavailability of PAS and the sodium, potassium, and calcium salts of PAS has been studied. Absorption of PAS and its three salts is essentially complete. Dissolution of PAS appears to be a rate-limiting factor in its absorption. The type of salt administered affects the rate of absorption. Although absorption of all four compounds was complete, the areas under the plasma concentration-time curve, or bioavailable drug, are dependent on the rate of absorption. The data presented show evidence of rate-limited metabolism, especially in the first pass.The work on which this publication is based was performed pursuant to Contract No. FDA 72-333 with the Public Health Service, Food and Drug Administration, Department of Health, Education and Welfare.     

Phase II study of oral bis (aceto) ammine dichloro (cyclohexamine) platinum (IV) (JM-216, BMS-182751) given daily x 5 in hormone refractory prostate cancer (HRPC)

JM-216 is an orally bioavailable platinum compound with activity against many tumor models. The objective of this study was to determine the safety profile and anti-tumor activity of JM-216 in patients with hormone refractory prostate cancer (HRPC) when given orally daily x 5 days. In this open label phase II study JM-216 was administered orally at the dose of 120 mg/m2/d for 5 days every 4 weeks. Patients continued on the therapy until evidence of disease progression or intolerable toxicity developed. Dose escalation and de-escalation were allowed according to patient's tolerance. Thirty-nine patients were enrolled onto the study and received a total of 155 courses (median 2, range 1-16) of JM-216. Dose delays (77% of courses) and dose reductions (31% of courses) were common and were mainly due to myelosupression. Treatment was discontinued in 5 patients due to treatment related toxicities. One patient developed myelodysplastic syndrome 11 months after the start of treatment. The most frequent grade III or higher adverse events included thrombocytopenia (54%), neutropenia (52%), anemia (24%) nausea (13%), vomiting (16%) and diarrhea (28%). PSA response was assessed in 32 patients, 10 (26%) had partial response, 14 (36%) had stable disease while PSA progression was seen in 8 (21%) patients. Of 20 (54%) patients with measurable disease two patients had a documented partial response. Although JM-216 had moderate activity in HRPC when given on daily basis for 5 days, it is associated with significant treatment related toxicities in this patient population.     

Evaluating Barriers to Bioavailability in Vivo: Validation of a Technique for Separately Assessing Gastrointestinal Absorption and Hepatic Extraction

PURPOSE: The purpose of this study was to develop and validate a method for separately evaluating the roles of gastrointestinal absorption and hepatic extraction as barriers to oral bioavailability (BA). The method was validated using five reference compounds known to have different absorption and hepatic extraction properties. Dose-dependence was also investigated for one reference compound. METHODS: Five reference compounds, amoxicillin, antipyrine, atenolol, propranolol, and testosterone, were administered as a cassette intravenouly (IV), via the hepatoportal vein (IPV), intraduodenally (ID), and intracolonically (IC) to male Sprague-Dawley rats. Blood samples were taken at nine time points, and the compounds were extracted from plasma using solid phase extraction. Plasma concentrations of each compound were determined using Liquid Chromatography Tandem Mass Spectrometry (LC/MS/MS). Pharmacokinetic parameters including bioavailability were calculated for each compound for each route of administration. RESULTS: Testosterone BA was less than 10% by ID, IC, and IPV routes, due to high hepatic extraction, consistent with its high systemic clearance (63 ml x min(-1) x kg(-1)) and short terminal plasma half-life (23 min). The IPV BA of amoxicillin was 95%+/-6% indicating the absence of hepatic extraction in the rat, but with an ID BA of approximately 39% suggesting incomplete GI absorption to be the main barrier to bioavailability. Absorption was poor from the colon, demonstrating site-dependence consistent with literature reports of site-dependent absorption. Low oral BA of propranolol was due in part to first-pass hepatic extraction (IPV BA of 36%). The IPV BA of propranolol was dose-dependent, most likely due to saturation of the P450 enzymes. Atenolol was incompletely bioavailable due to incomplete intestinal absorption, with no contribution of hepatic first-pass metabolism. Antipyrine was highly bioavailable by all routes. CONCLUSIONS: This in vivo rat model is demonstrated to be useful for identifying and quantifying the causes of incomplete bioavailabilty. It separately evaluates intestinal absorption, hepatic extraction, and site-dependent absorption. Concentration-dependence of saturable processes can also be examined.     

Zinc,copper and manganese in the organs of rats after sublethal cyanide intoxication

Single doses of sodium cyanide (60 mol/kg body weight s.c.) were administered to male Sprague-Dawley rats. The effect of this poison on the content of the trace elements zinc, copper and manganese was investigated in various organs after 30 min, 2 h, 24 h, 48 h and 1 week. The zinc content in the liver was elevated 24 h after this sublethal cyanide dose (by approximately 20%). In contrast, the copper content in the kidneys was lowered (by approximately 15%) at the same time. Almost similar changes were observed in the same organs after daily administration of the poison for 5 days. For comparison, another group of rats was allowed to respire for 30 min the air that contained only 10% oxygen. The above changes in the trace element concentrations were not observed under these conditions.After sublethal cyanide poisoning there seemed be slight but specific alterations in the trace element concentrations in the liver and kidneys of rats. On the other hand, there were no alterations in serum, heart, lung, brain, muscle, bone or testes. Up to now there is no clearcut explanation for the development and the possible biochemical importance of these results.     

非诺贝特胶囊(微粒化)人体生物利用度研究

目的评价非诺贝特胶囊(微粒化)2种制剂的生物等效性。方法24名健康男性志愿者单剂量随机交叉口服非诺贝特胶囊(微粒化)受试制剂160mg与参比制剂200mg,采用高效液相色谱法测定血药浓度,计算药动学参数和相对生物利用度。结果受试制剂与参比制剂的tmax分别为(3.91±1.00)、(3.74±0.86)h,Cmax分别为(10.33±3.26)、(10.61±2.79)μg/ml,AUC0~72分别为(173.54±56.04)、(176.69±47.13)(μg.h)/ml,t1/2分别为(22.25±3.78)、(23.19±3.71)h,受试制剂的相对生物利用度为(97.80±14.32)%。结论2种制剂具有生物等效性。     

HPLC法测定复方罗布麻片(II)中氢氯噻嗪的含量

建立用高效液相色谱法测定复方罗布麻片(II)中的氢氯噻嗪含量的方法。采用Hypersil C18柱为分析柱;流动相为乙腈-水(20∶80);流速为1.0 mL.min-1;检测波长为271 nm。线性范围为1.6848~8.4240μg.mL-1,r=0.9998,平均回收率为99.20%,RSD为0.3%(n=6)。本法简便、快速、可靠,可应用于复方罗布麻片(II)的质量控制。     

Absorption of Recombinant Human Granulocyte Colony-Stimulating Factor (rhG-CSF) from Rat Nasal Mucosa

Nasal absorption of recombinant human granulocyte colony-stimulating factor (rhG-CSF) was examined in the rat. The relative bioavailability of rhG-CSF for subcutaneous administration was 2%, as evaluated from the immunologically active rhG-CSF concentration in rat plasma and the area under the curve (AUC) of the plasma rhG-CSF concentration versus time for 8 hr. Pharmacological availability relative to subcutaneous administration was determined from the increase in total blood leukocyte numbers. The pharmacological availability was 5–10%, determined from the AUC for the increased ratio of total leukocyte numbers versus time for 48 hr; it was slightly dependent on the pH and the osmotic pressure of the dosing solution. Accordingly, the plasma concentration of rhG-CSF did not always reflect its pharmacological effects. Relative bioavailability and pharmacological availability were increased about 23 times and 3 times, respectively, by polyoxyethylene 9-lauryl ether (Laureth-9), but no increase in availability occurred with sodium glycocholate. The increase in total leukocyte numbers was maintained during multiple rhG-CSF dosing, and the addition of Laureth-9 further increased the pharmacological effects of this agent. This study indicates that nasal administration of rhG-CSF is an effective parenteral administration route.     

Evaluation of the Intestinal Absorption of Erythromycin in Man: Absolute Bioavailability and Comparison with Enteric Coated Erythromycin

To determine the role of acid hydrolysis on the gastrointestinal absorption of erythromycin, six healthy subjects received erythromycin as a 240 mg intravenous dose, a 250 mg oral solution administered via endoscope directly into the duodenum and bypassing the stomach, and an enteric-coated 250 mg capsule. Blood samples were collected for 6 hours and serum erythromycin quantified by a microbiological method. The time to achieve maximum serum concentrations for the solution was 0.25 ± 0.08 (mean ± SD) hours and for the capsule was 2.92 ± 0.55 hours. The absolute bioavailability of erythromycin from the capsule was 32 ± 7% and for the duodenal solution 43 ± 14%. The ratio of the areas under the serum erythromycin concentration-time curve of capsule to solution was 80 ± 28% (range 38 to 110%). There is substantial loss of erythromycin apart from gastric acid hydrolysis, which cannot be accounted for by hepatic first-pass metabolism. Attempts to further improve the oral bioavailability of erythromycin beyond 50% by manipulation of formulation are likely to be futile.     

Preparation and properties of selected Zn(II)-peptide complexes in suspension

The preparation and properties of low soluble, suspended Zn(II) complexes containing the selected peptides: tyroliberin (TRH), gonadorelin (GnRH), dalarelin and corticothropin (ACTH) were studied. The amount of Zn(II) bound by 1 muM of the selected peptide (n) was defined, as well as affinity of Zn(II) to the peptide (Ka) and the durability of the created complex Zn(II)-peptide (Kd). ACTH associated the highest amount of Zn(II), and GnRH the lowest one: 1 microM of ACTH complexed 0.81 microM +/- 0.03 Zn(II), the same quantity of GnRH-0.52 microM +/- 0.07 and TRH and dalarelin associated 0.75+/-0.03 and 0.79+/-0.02 microM of Zn(II), respectively. The closest affinity was stated between Zn(II) and GnRH (Ka=157.692+/-21.300 microM(-1)), the smallest-towards ACTH (Ka=1.136+/-0.042 microM(-1)). The lower amount of Zn(II) associated by the studied peptide, the higher was its affinity versus this metal (r=-0.942). The analysis of the kinetics of the Zn(II)-peptide linkage revealed that the most stable complexes with this metal were formed by GnRH (Kd=0.006+/-0.001 microM(-1)) and by dalarelin (Kd=0.020+/-0.001 microM(-1)). Zn(II) with GnRH complexes are about 147 times more durable than ACTH (Kd=0.880+/-0.033 microM(-1)) ones. It was established that the Zn(II)-peptide complexes were more stable in the case of lower molecular weight of the peptide (r=0.963), and the inferior number of the amino acid residues accessible in the peptide (r=0.967).     

Bioavailability of p-chlorophenoxyisobutyric acid (clofibrinic acid) after repeated doses of its calcium salt to humans

Summary Plasma concentrations and bioavailability of clofibrinic acid have been estimated under conditions approaching the steady-state during a ten-day period of administration as clofibrate or as a calcium clofibrinate-carbonate combination (1:1 w/w) at a dosage interval of 12 h. Formulation — related differences in bioavailability were not significant, and the 95% confidence limits of these differences were within –2% to +8% of the mean for the reference formulation of clofibrate. The mean steadystate plasma concentrations of clofibrinic acid measured on the tenth day of dosing were 116 µg/ml±22 S.D. and 119 µg/ml±23 S.D. after administration of 885 mg as clofibrate and the calcium clofibrinate-carbonate combination respectively. The peaks of mean plasma concentrations were 70 µg/ml±15 S.D., 119 µg/ml±32 S.D. and 131 µg/ml±26 S.D. on the first, fifth and tenth day of dosing with clofibrate, and 62 µg/ml±13 S.D., 127 µg/ml±S.D. and 143 µg/ml±25 S.D. on the corresponding days of dosing with the calcium clofibrinate-carbonate combination. After the last dose on the tenth day of dosing, the mean apparent half-lives of elimination of clofibrinic acid from plasma were 24.2 h±4.4 S.D. and 25.5 h±3.2 S.D. after administration of clofibrate and the calcium clofibrinate-carbonate combination respectively.     

Evaluation of changes in oral drug absorption in preterm and term neonates for Biopharmaceutics Classification System (BCS) class I and II compounds

Aims

Evidence suggests that the rate of oral drug absorption changes during early childhood. Yet, respective clinical implications are currently unclear, particularly for preterm neonates. The objective of this study was to evaluate changes in oral drug absorption after birth for different Biopharmaceutics Classification System (BCS) class I and II compounds to better understand respective implications for paediatric pharmacotherapy.

Methods

Two paradigm compounds were selected for BCS class I (paracetamol (acetaminophen) and theophylline) and II (indomethacin and ibuprofen), respectively, based on the availability of clinical literature data following intravenous and oral dosing. A comparative population pharmacokinetic analysis was performed in a step‐wise manner in nonmem® 7.2 to characterize and predict changes in oral drug absorption after birth for paracetamol, theophylline and indomethacin.

Results

A one compartment model with an age‐dependent maturation function for oral drug absorption was found appropriate to characterize the pharmacokinetics of paracetamol. Our findings indicate that the rate at which a drug is absorbed from the GI tract reaches adult levels within about 1 week after birth. The maturation function for paracetamol was found applicable to theophylline and indomethacin once solubility limitations were overcome via drug formulation. The influence of excipients on solubility and, hence, oral bioavailability was confirmed for ibuprofen, a second BCS class II compound.

Conclusions

The findings of our study suggest that the processes underlying changes in oral drug absorption after birth are drug‐independent and that the maturation function identified for paracetamol may be generally applicable to other BCS class I and II compounds for characterizing drug absorption in preterm as well as term neonates.     

The Bioavailability and Nonlinear Clearance of (–)-Carbovir in the Rat

The pharmacokinetics and bioavailability of (±)-carbovir, a carbocyclic nucleoside active against human immunodeficiency virus, have been described previously. To determine the bioavailability of (–)-carbovir, the biologically active enantiomer, four male Sprague–Dawley rats received 18 mg/kg of (–)-carbovir through the jugular vein and 54 mg/kg orally. Following the pilot studies, five rats were randomly assigned to receive (–)-carbovir in a three-way crossover design as either a single 18-mg/kg iv bolus, a single 54-mg/kg oral dose, or a single iv infusion of 18 mg/kg to achieve a target steady-state concentration (C _ss) of 1 µg/ml, the peak concentration after an oral dose. Blood and urine samples were analyzed by an improved ion-paired reversed-phase HPLC method with fluorescence detection. Blood concentrations of (–)-carbovir declined in a biphasic manner after the iv bolus dose. The terminal half-life was 116 and 106 min after the iv bolus and oral dose, respectively. The blood/plasma distribution ratio was approximately 1.0 in the range of 1 to 10 µg/ml of (–)-carbovir in blood. The free fraction in serum was concentration dependent. Significant differences in the renal, nonrenal, and total-body clearances after the iv bolus and iv infusion suggested nonlinear elimination of (–)-carbovir. The oral bioavailabilities derived from blood data were significantly different when the iv bolus was used as a reference rather than the iv infusion. However, the bioavailabilities were not significantly different when the total urinary excretion of unchanged (–)-carbovir after iv bolus or infusion was used as a reference. Concomitant saturation of renal and nonrenal clearances might explain these findings. The oral bioavailability was about 20% at concentrations approximating 1 µg/ml in blood.