Pharmacokinetics and tissue distribution of adriamycin and adriamycinol after intravenous administration of adriamycin-loaded neutral proliposomes to rats

Lee, Hee Jun; Ahn, Byung-N.; Yoon, Eunju; Paik, Woo Hyun; Shim, Chang-Su; Lee, Myung G.

doi:10.1016/0378-5173(94)00414-z

Cited by 20 publications

(18 citation statements)

References 20 publications

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“…Doxorubicinol is extensively distributed into tissues as its parent compound (14,33). The slight increases in the serum concentrations of doxorubicinol can probably be attributed to the redistribution of doxorubicinol from the tissues to the blood stream.…”

Section: Discussionmentioning

confidence: 99%

Effect of coenzyme Q10 on the disposition of doxorubicin in rats

Zhou

Chowbay

2002

Eur. J. Drug Metab. Pharmacokinet.

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The effect of exogenous coenzyme Q10 (CoQ10) on the pharmacokinetic profiles and biliary excretion of doxorubicin and its main metabolites, doxorubicinol and doxorubicinolone, was investigated in rats. No statistically significant changes in the pharmacokinetic parameters of doxorubicin was observed following the intravenous bolus administration of 10 mg/kg doxorubicin to rats during a 6-day oral regimen of CoQ10 (20 mg/kg daily). Treatment with CoQ10 did not affect the formation of the doxorubicinol, but produced a 75% increase (P < 0.05) in the AUC of doxorubicinolone. Correspondingly, CoQ10 had no apparent effect on the biliary excretion of doxorubicin and formation clearance of doxorubicinol, whereas the formation clearance of doxorubicinolone was significantly increased by 69% in CoQ10-pretreated rats (P < 0.05). Overall, the results suggest that CoQ10 treatment has no significant effect on the pharmacokinetics of doxorubicin and the formation of the cytotoxic metabolite, doxorubicinol.

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Section: Discussionmentioning

confidence: 99%

Effect of coenzyme Q10 on the disposition of doxorubicin in rats

Zhou

Chowbay

2002

Eur. J. Drug Metab. Pharmacokinet.

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“…Lee et al 1996 [45] Adriamycin (23214-92-8) Adriamycinol (54193-28-1) Uranyl nitrate induced ARF The plasma exposures of both adriamycin and adriamycinol were maintained at much higher levels and for a longer duration of time in ARF rats relative to control rats. This was accompanied by a decreased excretion of both adriamycin and adriamycinol in the urine samples.…”

Section: M2 M3 and M4)mentioning

confidence: 93%

“…Tissued istribution:T hereweretworeports thats uggested propensity forincreased accumulation in several tissuesin ARF rats.While the ratio of amountin tissue(s)/plasmac oncentration appeared tobeconsistent forDA-131 [42], itfavoured ARF rats foradriamycin (CAS 23214-92-9) [45].Inthe caseo fchlorzoxazone, wherethe metabolicc learancewasfasterin ARF rats, the levelsof the hydroxylchlorzoxazone metabolitebut notchlorzoxazone wered etected in the tissues [34].Interestingly,in arecents tudyof quinidine,oppositee ffects wereo bserved between twoARF models.While the glycerol induced ARF decreased the free fraction and volume of distribution of qunidine,the cisplatin induced ARF showed no alterationsin eitherthe free fraction orv olume of distribution of quinidine [15].…”

Section: 2distribution Related Changesmentioning

confidence: 98%

“…Renale xcretion:A sdocumented in all studiesane xpected outcome in ARF iss everereduction of renal clearanceapplicable tobothparentdrugand associated metabolites.Ifthe sole contributorand/ormajorpathwayfort he overall elimination isr enalclearance,then accumulation of the substrateisbound tohappen asexemplified bys ubstratess uchasetoposide (CAS 33419-42-0) [19], telithromycin (CAS 191114-48-4) [20], topotecan( CAS 123948-87-8) [26], adriamycin [45], etc.Inthe eventthatcertain CYP expressionsarealsoinduced during ARF, itispossible thatmetabolicc learanceo fthe drugafteroraldosing maygetmoreaffected thanintravenous dosing in ARF rats.Henced epending on the non-renalclearancep athways duetoe nhanced metabolism,the totalbodyclearancem aygets omewhat tempered asillustrated bys ubstratess uchasmycophenolica cid (CAS 24280-93-1) [22], DA-7867 [25], DA-125 [44]etc. Biliary excretion:A sillustrated byt wocasestudies bothp arentdrugand metabolite(s)canbep redominantlyexcreted viab iliary pathwayduring ARF.Since suchbiliary excretory pathways wereo fl imited applicability in control rats undernormalconditions,itappears thatARF conditionsmaypromptalternativee xcretory pathways forr educing the drugburden on the body.Asexemplified in the caseo fcyclosporine there maybed iminished bile secretion and pert he datagenerated from indocyanine green therem aybeasignificantdelayin the biliary excretion of the compound during ARF [68].Onthe contrary,the biliary excretion of 7-O-glucuronica cid conjugateo fm ycophenolica cid was significantlyincreased in ARF rats [22].Asaresultof rapid enterohepaticc ycling of the Phase2metabolite and poorr e-absorption from the lumen,therewasa suggestion of ani ncreased risko fg astrointestinald isorders [22].…”

Section: Changesr Elated Toe Xcretionmentioning

confidence: 99%

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Altered disposition of drugs in acute renal failure rat models: drug development strategies and perspectives

Srinivas¹

2011

Arzneimittelforschung

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In the evolving paradigm of drug development it is a reasonable strategy to avoid and/or anticipate potential risks in drug development for select drugs by performing in vitro and/or preclinical studies in appropriate animal models. The availability of acute renal failure (ARF) rat models provides an opportunity to explore the pharmacokinetic disposition of drugs and associated metabolites in conditions that mimic the pathophysiology of the disease in humans. Such studies may help in drug(s) selection for development, differentiating certain drug classes, and/or arriving at a dose strategy decision in the clinic. Scores of compounds, belonging to various therapeutic areas, have undergone pharmacokinetic investigations in ARF models induced by uranyl nitrate (CAS 10102-06-4), glycerol (CAS 56-81-5), cisplatin (CAS 15663-27-1) or gentamicin (CAS 1403-66-3) in rats. The published pharmacokinetic disposition data has unequivocally suggested that ARF conditions leads to decreased renal elimination of the drug and associated metabolites; however, the influence on the overall body clearance is dependent on the propensity of the contribution of renal versus non-renal mechanisms of elimination. In the case studies assembled for this review, 52.5% of the drugs showed an increased drug exposure, 35% of the drugs showed a decreased drug exposure and 12.5% of the drugs showed no altered exposure, in ARF rat models relative to control rats. Interestingly, ARF can have an overall impact on drug absorption, distribution, metabolism, local transport and biliary excretion. Hence, the overall pharmacokinetic disposition may have to be interpreted with caution during ARF since there is the potential for competiting pathways to co-exist. For instance, due to reduced renal elimination as a result of kidney insult caused by ARF, compensatory biliary excretion mechanism may occur. Alternatively, intestinal and/or hepatic enzymatic expression level may go up to facilitate enhanced metabolism. However, there may be instances where uraemic toxins floating in the circulation may block the metabolism and/ or may also retard the absorption process. This review covers: 1) an illustration of a number of case studies providing tabulated information on the key altered pharmacokinetic parameters observed in ARF and the hypothesized mechanistic explanation; 2) a comprehensive description of altered absorption, distribution, metabolism, excretion and efflux transport related changes observed during ARF; 3) a general framework for drug development strategies and 4) a succinct discussion on the overall perspectives of the applicability of ARF rat models.

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“…After the reviews, the pharmacokinetic and/or pharmacodynamic changes of furosemide [4], azosemide [5], DA-1131, a new carbapenem [6], DA-125, a new anthracycline [7] and adriamycin [8] in rats with DMIA have been reported.…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetic changes of diltiazem and desacetyldiltiazem after oral administration of diltiazem in rabbits with diabetes mellitus induced by alloxan

Choi

Kim

2002

Biopharm & Drug Disp

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Physiological changes occurring in diabetes mellitus patients could alter the pharmacokinetics of drugs used to treat hypertension resulting from diabetic complications. Hence, the pharmacokinetics of diltiazem (DTZ) and its metabolite, desacetyldiltiazem (DAD), were investigated after oral administration of DTZ. DTZ, 20 mg/kg, was orally administered to control rabbits and rabbits with fifth day (experiment was performed at fifth day after first and second days intravenous administration of alloxan) and 13th day (experiment was performed at 13th day after first, second, sixth, and 10th days intravenous administration of alloxan) diabetes mellitus induced by alloxan. Impaired kidney and liver functions were observed in both diabetic groups based on plasma chemistry data and/or tissue microscopy. After oral administration of DTZ, the area under the plasma concentration-time curve from time zero to time infinity were 767, 1280 and 1550 ng h/ml for control rabbits and fifth and 13th days diabetes mellitus rabbits, respectively. The values in diabetes mellitus rabbits were significantly different as compared to control rabbits. The terminal half-lives of DTZ were significantly longer in fifth (13.4 h) and 13th (13.0 h) days diabetes mellitus rabbits than that in control rabbits (8.76 h). The renal clearances of DTZ in fifth (0.3161/h/kg) and 13th (0.2641/h/kg) days diabetes mellitus rabbits were significantly slower than that in control rabbits (0.5051/h/kg), and this could be due to impaired kidney function in the diabetes mellitus rabbits. However, other pharmacokinetic parameters of DAD were not significantly different among three groups of rabbits.

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Pharmacokinetics and tissue distribution of adriamycin and adriamycinol after intravenous administration of adriamycin-loaded neutral proliposomes to rats

Cited by 20 publications

References 20 publications

Effect of coenzyme Q10 on the disposition of doxorubicin in rats

Effect of coenzyme Q10 on the disposition of doxorubicin in rats

Altered disposition of drugs in acute renal failure rat models: drug development strategies and perspectives

Pharmacokinetic changes of diltiazem and desacetyldiltiazem after oral administration of diltiazem in rabbits with diabetes mellitus induced by alloxan

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