2,2′,3′,4,4′,5,5′-Heptachlorobiphenyl (PCB 180) — on its toxicokinetics,biotransformation and porphyrinogenic action in female rats

The toxicokinetics and biotransformation of 2,2,3,4,4,5,5-heptachlorobiphenyl, as well as its influence on the activity of microsomal and cytosolic enzymes and on the porphyrin pathway in the liver were studied in female rats following oral treatment with 7 mg/kg every other day for 3 months. One day after cessation of treatment the concentration of the compound in liver, spleen, CNS and blood was 100–500 times and in the trachea it was only 5 times less than in the adipose tissue. The daily excretion with the feces and urine amounted to 35 and 1.5 g, respectively. In both excreta, heptachlorobiphenylol was identified as a metabolite. The biotransformation rate was estimated to be about 5%. Investigations of the liver revealed increases in the relative liver weight, total cytochrome P-450 content, O-deethylation of 7-ethoxycoumarin and in the activity of glutathione S-transferases. Disturbances of the hepatic porphyrin pathway were not detected. Only at the end of a post-dosing period of 12 months did the hepatic uroporphyrinogen decarboxylase show diminished activity. Only one of these animals with diminished enzyme activity showed drastically elevated porphyrins. In these animals, the fecal and urinary porphyrins did not differ from controls. At no time did heptachlorobiphenyl influence the urinary excretion of delta-aminolevulinic acid and porphobilinogen. The results indicate 1) that this congener shows expected toxicokinetics with the exception of being accumulated in the trachea and 2) that this congener induces disturbances of the hepatic porphyrin pathway several months after cessation of treatment.     

Induction of immunotoxicity in mice by polyhalogenated biphenyls

Acute administration of Aroclor-1254 (500 mg/ kg) or 3,4,5,3,4,5-hexabromobiphenyl (HBB) (2–6 mg/ kg) IP, profoundly inhibited the plaque forming response to subsequent challenge with sheep erythrocytes in Ah locus positive (C57B1/6N or B6C3F1N) mice. These studies showed: 1) the immunotoxicity results paralleled enzyme induction results insofar as HBB was approximately 100 times more potent than Aroclor 1254; (2) neither Aroclor nor HBB treatment caused significant induction in the Ah locus negative DBA/2N mice; 3) when B6C3F1 mice were challenged with sheep red blood cells (SRBC) 6 or 16 weeks post Aroclor 1254 treatment, substantial recovery of a PFC response was observed; 4) when these compounds were administered to older (76-week-old) (B6C3F1 mice, severe depression of a PFC response was observed. In contrast to its profound depression of a PFC response, Aroclor-1254 (up to 1250 mg/kg) caused slight increases in lymphocyte proliferation induced by either T or B cell mitogens. A single 500 mg/kg dose of Aroclor-1254 also suppressed the ability of recipient B6C3F1 animals to reject a challenge with either the syngenic fibrosarcoma (PYB6) or the gram negative pathogen (Listeria monocytogenes).     

Effects of indomethacin on changes in renal blood flow induced by adenosine and its analogues in conscious dogs

Summary The effects of indomethacin on changes in renal blood flow induced by adenosine, NECA (adenosine-5-N-ethyl-carboxamide) and 2,3-dinitro-NECA were investigated in 6 chronically instrumented conscious dogs. Adenosine (187.5, 375 and 750 nmol/kg, i.v.) induced a dose-dependent initial decrease, followed by a reactive increase in renal blood flow. NECA (1.5 nmol/kg, i.v.) also induced an initial decrease, which was, however, followed by a prolonged reactive increase in renal blood fow. 2,3-dinitro-NECA (50 nmol/kg, orally) induced only an increase in renal blood flow. Indomethacin (27.9 mol/kg, i.v.) caused no relevant change of the initial decrease and a significant attenuation of the reactive increase in renal blood flow induced by adenosine. NECA-induced changes in blood flow were affected by indomethacin in the same direction but to a greater extent than were adenosine-induced changes in blood flow. Indomethacin reversed the increase to a decrease in renal blood flow induced by 2,3-dinitro-NECA. Thus, prostaglandins seem to be involved in mediating the response of renal blood flow to adenosine, NECA and 2,3-dinitro-NECA.Part of this study was presented at the fall meeting of the German Pharmacological Society, September 1982 in Vienna, Austria     

Pharmacokinetics of 2′,3′-dideoxyadenosine in dogs

The pharmacokinetics of 2,3-dideoxyadenosine (ddAdo) and 2-3-dideoxyinosine (ddIno) were determined after intravenous bolus administration and long-term intravenous infusion of ddAdo in dogs. ddAdo was rapidly deaminated to ddIno and ddAdo plasma concentrations were only a fraction of ddIno concentrations. The total body clearance of ddAdo exceeded the literature value for the cardiac output of the dog, indicating an extremely rapid metabolism, and the existence of extrahepatic metabolism. Urinary excretion of unchanged ddAdo was a minor route of elimination ( 1%). The pharmacokinetics of ddIno was determined assuming complete conversions of ddAdo to ddIno. ddIno elimination was dose-dependent with total body clearance ranging from 4 to 55 ml/min/kg in individual animals. The plasma half-life was approximately 30 min after most routes of administration, but increased to approximately 60 min in two animals receiving a large intravenous dose of 500 mg/kg. ddIno penetrated into the cerebrospinal fluid to a limited extent, reaching concentrations of 3–11% of those in plasma. Urinary excretion of unchanged ddIno accounted for approximately 20% of the administered dose of ddAdo, while uric acid and hypoxanthine were minor urinary metabolites.Concentrations exceeding the in vitro minimal viral inhibitory concentration (2.4 g/mL) could be safely maintained in plasma for a 10-day period. Infusions which gave cerebrospinal fluid concentrations of 12 to 17 Lg/mL resulted in dose limiting myelosuppression and intestinal toxicity, after less than 10 days of infusion. Orally administered ddAdo was absorbed as ddIno, with bioavailabilities ranging from 28 to 93% in experiments where no emesis occurred. These studies indicate the rapid in vivo conversion of ddAdo to ddIno, and support the selection of ddIno over ddAdo for further drug development.     

Analytical Method for the Quantification of 2′,3′-Didehydro-3′-Deoxythymidine,a New Anti-Human Immunodeficiency Virus (HIV) Agent,by High-Performance Liquid Chromatography (HPLC) and Ultraviolet (UV) Detection in Rat and Monkey Plasma

Pharmaceutical Research -     

Effects of methacholine,histamine and atropine on pulmonary guanosine-3′, 5′-monophosphate levels in hypersensitive mice

Summary Pulmonary levels of cGMP and cAMP in mice sensitized to methacholine and histamine with b. pertussis were examined to determine whether sensitization could be the result of an alteration in the metabolism of these cyclic nucleotides. The results presented show that in sensitized mice, methacholine raised cGMP to levels that were about double those produced without sensitization. In analogous experiments, histamine raised cGMP by approximately 100% in sensitized mice without producing significant increases in nonsensitized groups. Atropine completely blocked the cGMP rises produced by methacholine but did not eliminate those produced by histamine, thus indicating that cholinergic, but not the histaminergic elevation of cGMP involves activation of muscarinic receptors. The influence of pertussis on cAMP appeared to be opposite in direction from cGMP, i.e., a small but significant drop in cAMP levels was found following methacholine administration to sensitized, but not to nonsensitized mice. It was concluded that pertussis sensitization increases the responsiveness of the pulmonary guanylate cyclase-cGMP system to methacholine and histamine, and that the altered patterns of cGMP accumulation may contribute to the biochemical mechanism of sensitization.     

A simple method for sampling murine pulmonary and cardiac tissues for analysis of cyclic nucleotide levels

Summary A simple method for the rapid removal and freezing of mouse cardiac and pulmonary tissues is described. Samples thus obtained were judged to be suitable for valid estimation of in vivo levels of cyclic AMP and cyclic GMP based on the following findings: (a) the samples could be obtained and frozen in the very short time period of a few seconds; (b) no indication of adverse effects of the collection procedure was found upon examination of chemical indicators of energy metabolism; (c) the apparent rates of change of cyclic AMP and cyclic GMP levels during the first seconds after tissue isolation could produce small, but acceptable errors; and (d) dose-dependent elevations of pulmonary cAMP levels consistent with known effects in vitro were found after in vivo administration of isoproterenol.Abbreviations cAMP adenosine-3,5-cyclic monophosphate - cGMP guanosine-3,5-cyclic monophosphate     

Disposition of 2′, 3′-dideoxyadenosine and 2′, 3′-dideoxyinosine in mice

Summary Mice were dosed with [³H]2,3-dideoxyadenosine ([³H]ddA) in three procedures: intravenously, intraperitoneally, and interperitoneally following a dose of 2 -deoxycoformycin (dCF). For mice dosed intravenously, the content of radioactivity in plasma and tissue samples were essentially constant after 30 min. Of the radioactivity in plasma and brain samples collected between 30 min and 24 hr, more than 94% was present as ³H₂O, indicating that most of the tritium from [³H]ddA had exchanged with water. No intact ddA was detected, and the deamination product, 2,3 -dideoxyinosine (ddI), was present only transiently. In the urine, the major radioactive material was [³H]ddI. Also detected were ³H₂O and small amounts of [³H]hypoxanthine and [³H]ddA. Following intraperitoneal doses to mice, levels of radioactivity in plasma, liver, and kidney increased to a maximum by 15–30 min after dosing but dropped to essentially constant levels thereafter, again indicating that the tritium had exchanged with water. At 5, 15, and 30 min after dosing, ddI was the major radioactive component in plasma. Only small amounts of ddA were present. When dCF was administered 24 hr prior to intraperitoneal [³H]ddA, levels of radioactivity in plasma, liver, and kidney reached a maximum at 30 to 60 min after dosing and decreased to essentially constant levels thereafter. The dCF transiently inhibited the deamination of ddA to ddI, since, in plasma, [³H]ddA was the main radioactive component at 5 and 15 min after dosing. Comparison of HPLC assays based on radioactivity detection and UV absorbance showed that they were equivalent for measuring ddA and ddI in samples derived from dosed mice. Therefore, exchange of tritium must have occurred at a metabolic step beyond ddI.For mice dosed intravenously and orally with unlabeled ddI, there was evidence of a saturated process. Nevertheless, for the high and low intravenous doses of ddI, the percent of dose excreted in the urine as unchanged drug was the same.     

Percutaneous Absorption of 2′,3′-Dideoxyinosine in Rats

This study explored the topical route for administering of 2,3-dideoxyinosine (ddI), a nucleoside analog used for treating patients with acquired immunodeficiency syndrome. A dose of ddI (180 mg/kg) dispersed in ~1 g ointment base was applied, with or without occlusion, to the back of high follicular density (HFD) and low follicular density (LFD) rats. The systemic ddI clearance was determined using a concomitant administration of an intravenous tracer dose of [³H]ddI. At 24 hr, the experiment was terminated and skin sections at the application site were removed. After topical application, average plateau plasma levels of about 0.6 µg/ml were achieved within 1 to 2 hr and maintained for 24 hr. Occlusion gave a more uniform plasma profile but did not increase the bioavailability. The systemic bioavailability in HFD and LFD rats was about the same at 33%. In addition, a depot of about 16% of the dose was recovered by rinsing the application area and extracting the drug from the excised application site. These data indicate that about 50% of the dermal dose penetrated the skin barrier in 24 hr. The similar bioavailability in the HFD and LFD rats further suggests an unimportant role for the transfollicular absorption route for ddI. The effect of a mixture of penetration enhancers, Azone and propylene glycol (5:95), was studied in HFD rats. Coadministration of ddI with the enhancers did not increase the ddI bioavailability. However pre-treatment and coadministration with the enhancers significantly increased the bioavailability to 62%, which is a conservative estimate because the plasma drug level was still at a plateau when the experiment was terminated at 24 hr. In summary, the transdermal bioavailability of ddI exceeded the 15% oral bioavailability found in previous studies by more than 3 folds and was further increased by the pretreatment with absorption enhancers. These data indicate the topical route as an attractive administration route.     

Effect of phenothiazine neuroleptic drugs and tricyclic antidepressants on phosphodiesterase activity in rat cerebral cortex

The activity of phosphodiesterase (PDE) of rat cerebral cortex following the administration in vitro and in vivo of various concentrations of neuroleptic phenothiazine drugs and tricyclic antidepressive drugs has been investigated. It has been shown that PDE activity is inhibited by phenothiazine neuroleptic drugs (fluphenazine > trifluperazine > thioproperazine > chlorpromazine = thioridazine). Tricyclic antidepressants nortriptyline, chlorimipramine, protiptyline, imipramine and desipramine at a concentration of 10^–3 M caused 60–80% inhibition of PDE activity. It has also been found that the investigated phenothiazine compounds inhibit the high affinity PDE activity more than the PDE activity of low affinity to the substrate.The results obtained suggest that the mechanism of the neuroleptic action of phenothiazine drugs is partially connected with their influence on cyclic 3,5-AMP metabolism.Supported by Polish Academy of Sciences, 09.4.1.5.     

Comparative studies on distribution and covalent tissue binding of 2,4,2′,4′- and 3,4,3′,4′-tetrachlorobiphenyl isomers in the rat

The ¹⁴C-labeled tetrachlorobiphenyl (TCB) isomers 2,4,2,4-tetrachlorobiphenyl (2,4,2,4-TCB) and 3,4,3,4-tetrachlorobiphenyl (3,4,34-TCB) were administered orally to rats, and distribution and covalent binding were measured in several organs. Marked differences in distribution and covalent binding of the two TCBs were observed. The accumulation and retention of 2,4,2,4-TCB in adipose tissue were much higher than those of 3,4,3,4-TCB, although the level of radioactivity in the blood was consistently higher in 3,4,3,4-TCB treated rats. The radioactivity bound in covalent linkages with cellular macromolecules in several tissues was also measured. The data obtained indicated that covalent binding was higher in 3,4,3,4-TCB treated rats than in those treated with 2,4,2,4-TCB, particularly in liver and blood components. These results suggest that the two TCB isomers have different pharmacokinetic properties in rats, and the association of covalent binding with 3,4,3,4-TCB-induced toxicities might be important. In addition, we found that repeated oral dosing with the two TCB isomers caused an increase in in vitro liver microsomal generation of reactive metabolites of TCBs, indicating that the microsomal enzyme system is likely to play an important role in the in vivo covalent binding of TCB.     

Pharmacokinetics of Oral 2′,3′-Dideoxyinosine in Rats

Pharmaceutical Research -     

In vitro activity of 4′ -iodo-4′ -deoxydoxorubicin on human colo-rectal cancer as measured by a short-term antimetabolic assay

Summary A short-term antimetabolic assay based upon the inhibition of incorporation of nucleic acid precursors was used to compare the cytotoxicity of a new halogenated anthracycline, 4-iodo-4-deoxydoxorubicin (IDX), with that of its parent compound doxorubicin (DX) on human colo-rectal carcinoma specimens. IDX showed a marked dose-dependent effect, with frequencies of activity consistently greater than those of DX at all concentrations. The minimal dose required to induce a significant antimetabolic effect for IDX was 1/10 that for DX.     

Bis(carbamoyloxymethyl) Esters of 2′,3′-Dideoxyuridine 5′-monophosphate (ddUMP) as Potential ddUMP Prodrugs

No HeadingPurpose. We previously reported the synthesis of bis(pivaloyloxymethyl) 2,3-dideoxyuridine 5-monophosphate (POM₂-ddUMP) (1a) as a membrane-transport prodrug formulation of the free parent nucleotide, ddUMP. Although successful at delivering ddUMP into cells in culture, POM₂-ddUMP was rapidly degraded by plasma carboxylate esterases after intravenous administration to experimental animals, and therefore has limited therapeutic potential as a systemically administered prodrug. We now report the synthesis of bis(N,N-dimethylcarbamoyloxymethyl)- and bis(N-piperidinocarbamoyloxymethyl) 2,3-dideoxyuridine 5-m onophosphate [DM₂-ddUMP (1b) and DP₂-ddUMP (1c), respectively], analogues of POM₂-ddUMP that were designed to be more resistant to degradation by plasma esterases..Methods. After entering cell by passive diffusion, it was anticipated that loss of one of the carbamoyloxymethyl groups of 1b and 1c would occur by spontaneous chemical hydrolysis to give the intermediate phosphodiesters, 2b and 2c. Cleavage of the remaining carbamoyloxymethyl groups by cellular phosphodiesterase I would generate ddUMP. 1b and 1c were prepared by condensation of 2,3-dideoxyuridine (ddU) with the appropriate bis(N-alkylcarbamoyloxymethyl) phosphate in DMA in the presence of triphenylphosphine and diethyl azodicarboxylate (the Mitsunobo reagent).Results. The half-lives of 1b and 1c when incubated at a concentration of 10^–4 M in human plasma at 37°C were 3.5 h and 3.7 h, respectively, similar to the half-lives observed under the same temperature conditions in 0.05 M aqueous phosphate buffer, pH 7.4. By contrast, the half-life of the POM₂ prodrug, 1a, in plasma was only 5 min. The initial products of degradation of 1b and 1c were the phosphodiesters 2b and 2c. The latter compounds gave rise to ddUMP when incubated with snake venom phosphodiesterase I.Conclusions. These findings support the premise inherent in the design of 1b and 1c, namely that the carbamate prodrugs are far more resistant to hydrolysis by plasma carboxylate esterases than their POM counterparts and can revert to the free parent 5-mononucletides by successive chemical and enzymatic hydrolysis. Further studies of 1b and 1c as membrane-permeable prodrugs of ddUMP are in progress.     

Cardiostimulatory effects of prenalterol,a beta-1 adrenoceptor partial agonist,in vivo and in vitro

Summary The cardiostimulatory effects of prenalterol, a beta-1-adrenoceptor partial agonist, were studied in vivo and in vitro and compared to those evoked by isoprenaline, a full agonist, and to those of other partial agonists.In the anaesthetized rat, prenalterol and terbutaline were found not to elevate the myocardial cyclic AMP content; this was in sharp contrast to isoprenaline. Both partial agonists did, however, produce significant effects on heart rate.In the anaesthetized cat, prenalterol exhibited chronotropic and inotropic intrinsic activities of 88 and 76% respectively in relation to isoprenaline. No statistically significant increase in myocardial cyclic AMP content could however be detected.Prenalterol did not stimulate adenylate cyclase significantly in the cat myocardial homogenate. This was also true of the beta-2-adrenoceptor selective partial agonist procaterol. In this preparation, isoprenaline, noradrenaline and adrenaline acted as full agonists. Furthermore, prenalterol produced a concentration-dependent inhibition of isoprenaline-activated adenylate cyclase.Our data indicate that maximal cardiac stimulation occurs at a low level of adenylate cyclase activation and low myocardial cyclic AMP concentration when provoked by a full beta-adrenoceptor agonist. The maximal physiological effects of a partial agonist such as prenalterol may consequently be achieved at a marginal activation of the adenylate cyclase.The present data may thus support the hypothesis of a large beta-adrenoceptor reserve for full agonists in the heart.     

Evaluation of cardiotoxicity of a new anthracycline derivative: 4′ -deoxy-4′ -iodo-doxorubicin

Summary The present study in rats was performed to evaluate the cardiotoxic activity of 4 -deoxy-4 -iodo-doxorubicin (4-deoxy-4-I-DXR), a new anthracycline derivative with interesting antineoplastic properties and possible lower cardiotoxicity than doxorubicin (DXR). DXR produced ECG alterations consisting of a progressive and irreversible prolongation of SaT and QaT. In contrast, in 4-deoxy-4-I-DXR-treated rats the increase in SaT and QaT duration was significantly lower than that observed in DXR-treated rats and slightly increased over controls.DXR produced significant histologic changes in myocardium consisting of myocyte vacuolization and myofibrillar loss. No significant modifications were observed in mitochondria. In contrast, no significant cardiac lesions were observed in 4-deoxy-4-I-DXR-treated rats. These results suggest that this new anthracycline derivative has a significantly lower degree of cardiotoxic activity than DXR.     

Phase II study of 4′-deoxydoxorubicin in advanced colorectal cancer

Summary Thirty-three patients with advanced colorectal cancer were entered on a phase II study of 4'-deoxy-doxorubicin (esorubicin) (30–35 mg/m² q 3 weekly). Objective response was documented in 4 of 25 previously untreated patients and in none of 8 previously treated patients. Toxicity was acceptable with grade 3 or 4 leukopenia occurring in 8 patients. Complete alopecia occurred only in 4 patients and gastro-intestinal toxicity was mild. A significant decrease (> 10%) of the left ventricular ejection fraction occurred in 8/23 patients who received > 2 courses of treatment.     

Effect of six virustatic nucleoside analogues on the development of fetal rat thymus in organ culture

The effects of the virustatic agents zidovudine (azidothymidine, AZT) 23-dideoxycytidine (ddC), 23-dideoxyinosine (ddI), acyclovir (ACV), ganciclovir (GCV), and vidarabine phosphate (VP) on the in vitro development of thymic lobes of 17-day-old rat fetuses were tested in an organ culture system. The virustatics were added to the medium for a culture period of 7 days. All nucleoside analogues inhibited the proliferation and differentiation of lymphatic cells. However, differences were observable with respect to the potency of the six drugs to interfere with thymic development. Compared to untreated controls, reduction in the number of thymocytes was significant at concentrations of 30 M AZT and ddI. In the case of ACV, GCV, VP, and ddC concentrations as low as 10 M were sufficient to cause a significant reduction, ddC being the most potent derivate. Increasing concentrations of the nucleoside analogues led to a dose-dependent further inhibition of cell proliferation. At a concentration of 30 M flow cytometry revealed a decrease in the relative number of double positive CD4⁺ CD8⁺ and single positive CD4⁺ CD8^– cells but an increase in the relative number of CD4-CD8⁺ cells. At the same concentration the expression of the CD5 antigen was reduced by the antimetabolites, indicating that maturation of the thymocytes was inhibited. Distribution of the forward light scatter, a cell size-related parameter, showed that the formation of small thymocytes was reduced by the nucleoside analogues. Light and electron microscopic investigations indicated cytotoxic effects of the drugs on the thymocytes, whereas the epithelium was only slightly affected.     

Adenosine receptor activation by adenine nucleotides requires conversion of the nucleotides to adenosine

Summary Adenine nucleotides cause adenosine receptor-mediated increases in cyclic AMP in the VA13 human fibroblast line. Levels of adenosine accumulated in the medium are insufficient to account for the responses to adenine nucleotides. Since rapid conversion of the nucleotides to adenosine by 5-nucleotidase in the vicinity of the receptor might account for the responses, six experimental methods were developed to distinguish between local conversion and direct action of the nucleotides. Results of all six methods favored local conversion. (1) 5-Nucleotidase inhibitors blocked the accumulations of cyclic AMP elicited by AMP, ADP, and ATP, but did not affect the response to adenosine. The most potent inhibitor of both conversion of AMP and response to AMP was ,-methylene-ADP (APCP). (2) Adenosine deaminase blocked the responses to AMP, ADP, ATP, and adenosine-containing coenzymes. (3) Theophylline, a specific competitive adenosine antagonist, was an insurmountable inhibitor of the increases in cyclic AMP caused by AMP, ADP, and ATP. The insurmountability was presumably due to substrate sataration of the converting enzyme 5-nucleotidase. (4) Although ADP and ATP had partial agonist-like dose-response curves, they did not inhibit the response to adenosine. (5) Nine cell lines which responded to adenosine were tested for response to AMP. Cell lines with high levels of 5-nucleotidase had large responses to AMP, those with intermediate levels of 5-nucleotidase had large or intermediate responses to AMP, and those with low 5-nucleotidase levels did not respond to AMP. (6) Inhibition of the uptake of labelled adenosine was used as an indicator of unlabelled adenosine concentrations near the cell membrane. Unlabelled AMP inhibited uptake nearly as effectively as unlabelled adenosine. APCP reversed the inhibition by AMP but not the inhibition by adenosine.The adenosine receptor is concluded to be an enity distinct from adenine nucleotide receptors.Submitted in partial fulfillment of the requirements for the degree Doctor of Philosophy in Neurosciences, University of California, San Diego. Supported by NIMH DA-00265 and PHS RR 05665. The author has been a NSF Graduate Fellow. An abstract of this material has been published (Bruns 1977)     

Pharmacokinetic Interaction Between Intravenous 2′,3′-Dideoxyinosine and Pentamidine in Rats

Purpose. This study examined the pharmacokinetic interaction between 2',3'-dideoxyinosine (ddl) and pentamidine. Background, ddl and pentamidine are often coadministered to patients with acquired immunodeficiency syndrome, and are both associated with pancreatic toxicity. Information on potential interaction would be useful to assess the need for dose modification and the basis of the higher incidence of pancreatic toxicity associated with coadministration of the two drugs. Methods. ddl (200 mg/kg) and pentamidine (10 mg/kg) were administered by continuous infusion to rats over 3 hr, either alone or concomitantly. Drug analysis was by high pressure liquid chromatography with UV or fluorescence detection, or by radioimmunoassay. Results. Pentamidine coadministration significantly increased the apparent volume of distribution at steady state of ddl from 1.4 to 3.4 l/kg (p = 0.004), and increased the mean residence time from 36.3 to 50.0 min (p = 0.015). Pentamidine enhanced the distribution of ddl from plasma into pancreas (p = 0.001) and muscle (p = 0.026). ddl distribution into spleen and liver was also increased, with differences approaching statistical significance (p = 0.08 and 0.06, respectively). In contrast, ddl coadministration did not affect the total body clearance but increased the urinary excretion and the renal clearance of pentamidine by about 5-fold (p = 0.0003). Conclusions. These data indicate that pentamidine increased the distribution of ddl into pancreas and muscle, whereas ddl increased the renal elimination of pentamidine.