The effect of anti-cancer drugs on pharmacokinetics of antipyrine in vitamin A deficiency

The pharmacokinetics of orally and intravenously administered antipyrine-¹⁴C in individual rats were investigated to examine the effects of vitamin A deficiency and/or cytotoxic anti-cancer drugs, like cyclophosphamide, methotrexate, 5-fluorouracil and actinomycin-D. Both vitamin A deficiency and pretreatment of rats with anti-cancer drugs led to impairment in the absorption from the gastro-intestinal tract and the plasma elimination of antipyrine. Pretreatment of vitamin A deficient rats with anti-cancer drugs further retarded the absorption and plasma clearance of antipyrine. Apparent volume of distribution of antipyrine was reduced (P < 0.001) by inducing vitamin A deficiency in rats. whereas pretreatment of rats with anti-cancer drugs did not show any effect.Cytotoxic drugs, and vitamin A deficiency increased the area under the plasma concentration vs. time curve of orally administered antipyrine (AUC_oral). In vitro findings suggest that the most probable cause of delayed clearance/prolonged half-life and increased AUC_oral values was the reduction in hepatic cytochrome P-450 dependent mixed function oxidase system.     

Pharmacokin?tics of intravenous and oral cyclophosphamide in the presence of methotrexate and fluorouracil

Cyclophosphamide was administered to 12 breast cancer patients in combination with methotrexate and fluorouracil. Doses prescribed were cyclophosphamide 75 mg/m², methotrexate 30 mg/m² and fluorouracil 500 mg/m² (per square meter body surface). Cyclophosphamide was administered intravenously and orally in aqueous solutions and in tablets in a randomized cross-over trial. Methotrexate and fluorouracil were administered intravenously, methotrexate was given first and then fluorouracil. Assays of cyclophosphamide in blood plasma were performed by capillary gas chromatography. Data of mean bioavailability of cyclophosphamide administered by tablets were suggestive of sufficient absorption. In 2 patients, however, a lower bioavailability of cyclophosphamide was demonstrated. Intra-individual differences in the terminal slope of the plasma decay curves after intravenous and oral administration in some patients decreased the calculated bioavailability of cyclophosphamide, if these values were included in the calculation of cyclophosphamide bioavailability. Compared with the administration of the solutions peak times, lag-times and mean absorption times of cyclophosphamide given in tablets were markedly prolonged. It is concluded that interactions between cyclophosphamide and methotrexate and/or fluorouracil after oral dosing as tablets are different from interactions observed after intravenous administration of cyclophosphamide.     

Life-threatening interaction between the root extract of Pueraria lobata and methotrexate in rats

Isoflavone supplements are nowadays widely used as alternative for hormone replacement therapy. However, the safety remains unanswered. This study attempted to investigate the effect of Pueraria lobata root decoction (PLRD), an isoflavone-rich herb, on the pharmacokinetics of methotrexate (MTX), a bicarboxylate antimetabolite with narrow therapeutic window. Rats were orally and intravenously given methotrexate alone and coadministered with PLRD. Blood samples were withdrawn via cardiopuncture at specific time points after drug administration. Serum methotrexate concentrations were assayed by specific monoclonal fluorescence polarization immunoassay method. Pharmacokinetic parameters were calculated using noncompartment model of WINNONLIN for both oral and intravenous data of MTX. Our results showed that coadministration of 4.0 g/kg and 2.0 g/kg of PLRD significantly increased the AUC(0-t) by 207.8% and 127.9%, prolonged the mean residence time (MRT) by 237.8 and 155.2%, respectively, finally resulted in surprisingly high mortalities of 57.1% and 14.3% in rats. When MTX was given intravenously, the coadministration of PLRD at 4.0 g/kg significantly increased the half-life by 53.9% and decreased the clearance by 47.9%. In conclusion, the coadministration of PLRD significantly decreased the elimination and resulted in markedly increased exposure of MTX in rats.     

Microsomal metabolism of antipyrine in rats treated with antineoplastic drugs

Pretreatment with antineoplastic drugs for at least 1 week is known to reduce in vivo metabolic clearance of antipyrine in rats tested after 24 h of fasting and restraining. In this study hepatic metabolism of 14C-antipyrine was investigated in 9,000 g supernatants of fed, unrestrained rats pretreated with cyclophosphamide, 5-fluorouracil or methotrexate. Total antipyrine metabolites formed were measured by a radiometric assay. Apparent Vmax and Km values were estimated and transformed to intrinsic (hepatic) clearance and total (body) clearance for comparison with in vivo terms of metabolic rate. Hepatic microsomal metabolism of antipyrine in control rats expressed as intrinsic clearance, 0.12 +/- 0.03 ml (g liver min)-1, and total clearance, 4.8 +/- 1.2 ml (kg body wt min)-1, was not significantly changed after antineoplastic pretreatment, indicating that the previously observed inhibitory action of these drugs on in vivo antipyrine metabolism may be modulated by factors such as fasting and stress.     

Effects of Capsaicin on the Pharmacokinetics of Antipyrine,Theophylline and Quinine in Rats

Abstract— Capsaicin is the active principal of capsicum fruits, such as hot peppers. The influence of 1-week pretreatment of capsaicin (25 mg kg^?1) on the pharmacokinetics of antipyrine, theophylline and quinine was investigated in rats. The drugs were given as an intravenous bolus dose. The control rats received the vehicle solvent (polyethylene glycol) only. Clearance of antipyrine in the capsaicin-pretreated rats was significantly lower than that observed in the control rats (0·241 ± 0·029 vs 0·344 ± 0·034 L h^?1 kg^?1, P < 0·05). This is consistent with a prolongation in the elimination half-life of antipyrine in animals pretreated with capsaicin (2·06 ± 0·30 vs 1·61 ± 0·27 h), as the volume of distribution was not significantly changed. In contrast, capsaicin pretreatment had no significant effect on the pharmacokinetics of theophylline and quinine.     

Assessment of the hepatic and intestinal first-pass metabolism of midazolam in a CYP3A drug-drug interaction model rats

In the current study, to understand the characteristics of dexamethasone (DEX)-treated female rats as an animal model for drug-drug interactions, a double-cannulation method was applied and separately assessed for the intestinal and hepatic first-pass metabolism of midazolam. Midazolam was administered intravenously or orally to the animals, and midazolam concentrations in the portal and systemic plasma were simultaneously determined. Next, the rates of elimination from the intestine and liver were estimated using the AUC values. After oral administration of midazolam, the entire drug was absorbed without intestinal first-pass metabolism, and 93% of the administered midazolam was extracted in the liver of the DEX-treated female rats. Seven per cent of the midazolam administered reached the systemic circulation. When ketoconazole was given orally to the animals, in conjunction with midazolam, the extraction ratio in the liver decreased from 93% to 77% in the control rats, and the bioavailability of midazolam increased to 23%. On the other hand, after intravenous administration, the elimination half-life of midazolam was not changed by ketoconazole pretreatment. These results indicated that midazolam is only extracted in the liver of DEX-treated female rats and that ketoconazole inhibits the hepatic first-pass metabolism, but not the systemic metabolism. In conclusion, DEX-treated female rats can be used as a drug-drug interaction model via CYP3A4 enzyme inhibition, especially for the hepatic first-pass metabolism of orally administered drugs.     

Effect of ranitidine on the disposition of orally and intravenously administered triazolam

The effect of orally administered ranitidine on the pharmacokinetic properties of orally and intravenously administered triazolam was determined. Twelve healthy males with a mean age of 35 years were enrolled in this four-way, randomized, crossover study. Each subject received a total of four treatments, each separated by one week. The treatments consisted of (1) one orally administered 0.25-mg triazolam tablet after treatment with ranitidine; (2) one orally administered 0.25-mg triazolam tablet, with no ranitidine pretreatment; (3) a 0.25-mg intravenous dose of triazolam after treatment with ranitidine; and (4) a 0.25-mg intravenous dose of triazolam, with no ranitidine pretreatment. Ranitidine pretreatment consisted of five 150-mg oral doses (as the hydrochloride salt) given every 12 hours; the last dose was given two hours before triazolam was administered. Blood samples were taken at intervals up to 12 hours after triazolam treatment. Serum triazolam concentrations were measured by modified high-performance liquid chromatography, and pharmacokinetic values were calculated. Pretreatment with ranitidine had no effect on the disposition of intravenously administered triazolam but significantly increased the area under the serum drug concentration-time curve of oral triazolam. Ranitidine pretreatment had no effect on triazolam's terminal elimination rate constant or on the time to reach maximum serum triazolam concentration. Ranitidine pretreatment increased the systemic availability of triazolam by increasing its absorption.     

Pharmacokinetics of atorvastatin and its hydroxy metabolites in rats and the effects of concomitant rifampicin single doses: relevance of first-pass effect from hepatic uptake transporters, and intestinal and hepatic metabolism.

Pharmacokinetic coadministration experiments with atorvastatin (ATV) and rifampicin (RIF) in rats were performed to investigate the potential involvement of hepatic uptake transporters, Oatps (organic anion-transporting polypeptides), during hepatic drug elimination, as an in vivo extension of our recently published cellular and isolated perfused liver studies. ATV was administered orally (10 mg/kg) and intravenously (2 mg/kg) to rats in the absence and presence of a single intravenous dose of RIF (20 mg/kg), and pharmacokinetic parameters were compared between control and RIF-treatment groups. RIF markedly increased the plasma concentrations of ATV and its metabolites when ATV was administered orally. The area under the plasma concentration-time curve (AUC(0-infinity)) for ATV also increased significantly after intravenous dosing of ATV with RIF, but the extent was much less than that observed for oral ATV dosing. Significant increases in plasma levels were observed for both metabolites as well. The 7-fold higher AUC ratio of metabolites to parent drug following oral versus intravenous ATV dosing suggests that ATV undergoes extensive gut metabolism. Both hepatic and intestinal metabolism contribute to the low oral bioavailability of ATV in rats. In the presence of RIF, the liver metabolic extraction was significantly reduced, most likely because of RIF's inhibition on Oatp-mediated uptake, which leads to reduced hepatic amounts of parent drug for subsequent metabolism. Gut extraction was also significantly reduced, but we were unable to elucidate the mechanism of this effect because intravenous RIF caused gut changes in availability. These studies reinforce our hypothesis that hepatic uptake is a major contributor to the elimination of ATV and its metabolites in vivo.     

Pharmacokinetics of SDZ 64-412, a novel antiasthmatic agent,following intravenous,oral, and inhalation dosing in the rat

The pharmacokinetics of SDZ 64–412, an antiasthmatic agent, were investigated following intravenous, oral, and inhalation dosing in rats. ¹⁴C-SDZ 64–412 was administered intravenously (2.75 mg kg^?1) and orally (5.5 mg kg^?1, 110 mg kg^?1), whereas non-radiolabeled drug (5.04 mg kg^?1) was administered using nose-only inhalation chambers. Radioactivity and parent drug concentrations in blood, lung, and excreta were determined at designated times post-dose. SDZ 64–412 was rapidly and extensively (～80%) absorbed following both oral doses, although absorption appeared to be prolonged with increasing dose. The absorbed drug was shown to undergo extensive and saturable first-pass metabolism. The bioavailability of the parent drug, calculated by dose-normalized AUC and deconvolution methods, was only 10–15% from the low dose, but increased to ～40% following the high dose. Following inhalation dosing, SDZ 64–412 concentrations in blood and lungs increased rapidly, and did not decline immediately after termination of dosing. The inhalation dose yielded a bioavailability of ～40%, and AUC of the drug in lungs was approximately 25 times greater than in blood. In general, SDZ 64–412 was extensively distributed and rapidly eliminated from the systemic circulation. Biliary excretion was the predominant route of radioactivity excretion. The present findings suggest that inhalation administration provides a viable means of delivery of SDZ 64–412.     

Pharmacokinetics of halofantrine in the rat: stereoselectivity and interspecies comparisons

The antimalarial drug, halofantrine, is chiral and is administered clinically as the racemate. In order to define the pharmacokinetic properties of halofantrine enantiomers in the rat, male Sprague-Dawley rats (264-311 g) were given halofantrine HCl orally (n = 5; 14 mg/kg) or intravenously (i.v.) (n = 5; 2 mg/kg). Plasma samples were collected over a 72 h period, and these were assayed for halofantrine enantiomer concentrations using a stereospecific reverse phase HPLC assay. After dosing by both routes of administration the (+) enantiomer was found to have significantly higher AUC, and higher Cmax after oral dosing. Pharmacokinetic analysis indicated that in the rat, the (+) enantiomer is cleared slower, and is less extensively distributed than its antipode. The bioavailability of the enantiomers after oral administration was less than 27%. Urinary excretion was a negligible route of elimination of unchanged drug. Using allometry, the pharmacokinetics of (+/-)-halofantrine in rats scaled nicely with literature data from dogs and humans. The pharmacokinetic properties of halofantrine enantiomers in the rat resembled those seen in humans, indicating that the rat is a good model for the study of halofantrine pharmacokinetics.     

Non-induction of extrahepatic antipyrine and metronidazole metabolism evaluated from partially hepatectomized rats

1. The effect of β-naphthoflavone (BNF), given i.p. (n = 9) and orally (n = 9), on the metabolism of antipyrine and metronidazole was investigated in rats.

2. The clearances of antipyrine and metronidazole were determined on a single saliva sample. The rates of formation of antipyrine and metronidazole metabolites were determined from a 20?h urine sample and saliva clearance.

3. Administration of β-naphthoflavone i.p. was significantly more effective than oral dosage on the induction of antipyrine and metronidazole metabolism (p<0.05).

4. The capacity of extrahepatic tissues to metabolize antipyrine and metronidazole was quantitatively assessed in rats with and without pretreatment with β-naphthoflavone immediately after sham operation or 70% partial hepatectomy (n = 40).

5. Antipyrine and metronidazole clearances correlated with liver weight in induced and non-induced rats. Linear regression of antipyrine and metronidazole clearances did show a non-significant Y-intercept (p>0.05), indicating a negligible extrahepatic metabolism in both induced and in non-induced rats.

6. From a quantitative point of view this study indicates that induction of extrahepatic cytochrome P450 metabolism of antipyrine and metronidazole is negligible.     

Pharmacokinetics of alpha-naphthyl isothiocyanate in rats

Many naturally occurring and synthetic isothiocyanates can inhibit chemical carcinogenesis in animal models. Recently, we found that alpha-naphthyl isothiocyanate (1-NITC) inhibited P-glycoprotein- and multidrug resistance associated protein 1-mediated efflux, indicating the potential application of 1-NITC as a chemosensitizing agent for cancer chemotherapy. The objective of this study was to explore the pharmacokinetic characteristics of 1-NITC in rats. A single dose of 10, 25, 50, or 75 mg/kg of 1-NITC was administered intravenously or orally to female Sprague-Dawley rats (n = 4 for each group). Dose-normalized concentration-time profiles were not superimposable following intravenous or oral dosing, indicating that the disposition of 1-NITC in rats was nonlinear. As doses increased from 10 to 75 mg/kg following iv administration, the total clearance decreased from 2.2 +/- 0.9 to 0.8 +/- 0.3 L/h/kg; oral availability averaged 0.46 for oral doses of 10-75 mg/kg. A nonlinear two-compartment open model with capacity-limited absorption and capacity-limited elimination from the central compartment best fit the data, based on goodness-of-fit criteria. The mechanism underlying the nonlinear elimination of 1-NITC in rats is most likely due to the capacity-limited metabolism of 1-NITC. This study represents the first report of the pharmacokinetics of 1-NITC.     

Oral and intravenous trichloroethylene pharmacokinetics in the rat

The pharmacokinetics of trichloroethylene (TCE) was studied in male Sprague-Dawley rats (300-350 g). TCE was administered intravenously and orally at doses of 5, 10, and 25 mg/kg to nonfasted rats and orally at 10 mg/kg to rats fasted for 8-10 h. The disappearance of TCE from the blood of intravenously dosed animals was best described by a two-compartment open pharmacokinetic model. The volume of the central compartment (Vc) approximated the rats' blood volume (50-70 ml/kg). The volume distribution (V beta) and total body clearance (CLT) decreased with increase in dose. The terminal half-life (t1/2) was about 120 min and was not affected by increases in dose. TCE was rapidly absorbed after oral dosing, with blood concentrations peaking between 6 and 10 min. The oral to intravenous bioavailability of TCE was 60-80% in nonfasted animals. The terminal t1/2 in fasted, orally dosed rats was identical to that when fasted rats were given the same dose intravenously. In fasted rats, bioavailability of an oral dose was greater than 90%, and peak levels in the blood were 2-3 times as high as in nonfasted rats.     

Changes in the disposition of promethazine during multiple dosing in the rabbit

During a multiple dosing regimen, the area under the promethazine blood concentration-time profile progressively decreased indicating auto-induction of metabolism. The increase in promethazine clearance (mean 35%) was not reflected in changes in either elimination half-life or minimum blood concentrations during the dosing interval. This was attributed to a deep compartment in the disposition of promethazine in the rabbit. The changes in promethazine clearance were accompanied by proportionally larger changes in the clearance of the monodesmethylpromethazine metabolite. The effect of promethazine pretreatment on the clearance of antipyrine was also studied and was found to be significantly increased by a mean of 17% following pretreatment with promethazine. However, the changes in the clearance of antipyrine did not highly correlate with those of promethazine and monodesmethylpromethazine. This may indicate that promethazine induces metabolic systems in the rabbit for which antipyrine is not a good substrate.     

Effect of ursodeoxycholic acid on the pharmacokinetics of midazolam and CYP3A in the liver and intestine of rats

1. The elimination half-life of midazolam administered intravenously (5 mg kg^?1) or orally (15 mg kg^?1) was significantly decreased by 70% and 73%, respectively, 24 h after a single oral administration of ursodeoxycholic acid (UDCA, 300 mg kg^?1) in rats. In the liver there was a significant enhancement of the hydroxylation of midazolam in the microsomes and expression of cytochrome P450 (CYP) 3A1 messenger RNA (mRNA) and CYP3A2 mRNA.

2. The C_max and area under the curve (AUC)_0–∞ of midazolam were significantly (1.8–2.3 fold) increased by the single oral treatment with UDCA (100 and 300 mg kg^?1). Thus, the oral bioavailability, estimated from the AUC_0–∞, of midazolam administered intravenously and orally was significantly (1.8- and 2.3-fold, respectively) increased by the treatment with UDCA.

3. Repeated administration of UDCA (300 mg kg^?1 day^?1) for 7 days did not alter the pharmacokinetics of midazolam administered intravenously or orally, and the expression of mRNA for CYP3As in the rat liver.

4. The study has shown that a single administration of UDCA in rats induces significant hepatic CYP3A activity and increases significantly the oral bioavailability of midazolam. Such effects on the pharmacokinetics of midazolam were little observed on the repeated administration of UDCA.

     

Variability of oral bioavailability for low dose methotrexate in rats.

The effects of food, antibiotics, diclofenac sodium (DS) and methotrexate (MTX) on oral bioavailability (BA) of MTX were examined in rats. Feeding didn't vary the plasma concentrations after intravenous dosing of 0.5 mg/kg MTX, but enhanced those after oral dosing, and the oral BA. The twice daily oral doses of 40 mg/kg neomycin sulfate (NS) or mixed antibiotics (200 mg/kg NS + 200 mg/kg streptomycin sulfate + 200 mg/kg bacitracin) for 5 days didn't influence the plasma concentrations after intravenous dosing of 0.5 mg/kg MTX, but induced the decreased Cmax and the delayed MRT after oral dosing. The plasma concentrations after intravenous or oral dosing of 2.5 mg/kg MTX in rats orally dosed with 1 or 5 mg/kg/day DS for 4 days were similar to those in the control rats, while the pre-treatment of 25 mg/kg/day DS delayed the elimination of MTX but didn't change the oral BA. The plasma concentrations after intravenous or oral dosing of 2.5 mg/kg MTX in rats, which received the intermittent oral doses of 7.5 mg/kg/3 doses/week MTX for 4 weeks, were comparable to those in the control rats, but the daily pre-treatment of 0.2 mg/kg/day MTX for 4 weeks increased the plasma concentrations after oral dosing, and the BA.     

In vivo inhibition of oxidative drug metabolism by, and acute toxicity of, 1-aminobenzotriazole (ABT). A tool for biochemical toxicology

One hour following intravenous pretreatment of rats with 50 mg/kg of the cytochrome P-450 suicide substrate 1-aminobenzotriazole (ABT), the metabolism of phenacetin to acetaminophen is inhibited completely [B. A. Mico et al., Drug Metab. Dispos. 15, 274 (1987)]. Here we report an examination of the time-course of inhibition of phenacetin elimination by ABT, a demonstration of dose-dependent inhibition of phenacetin and antipyrine clearances by ABT, and an examination of the acute toxicity of ABT in rats, as well as the effect of ABT on phenacetin metabolism in beagles. After a 1-, 12-, 24- or 36-hr pretreatment of rats with ABT (50 mg/kg, i.v.), the clearance of phenacetin was decreased 85, 88, 81 and 48%, respectively, from control values. Twelve hours after intraperitoneal pretreatment of rats with 0.3, 1.0, 5.0, 20, and 50 mg/kg of ABT, the total systemic clearance of phenacetin was suppressed 39, 47, 60, 75, and 79%, respectively, from control values. The clearance of intravenously administered antipyrine was decreased 38 and 66% after a 12-hr intraperitoneal pretreatment of rats with 10 or 50 mg/kg of ABT. In rats, no hematological, clinical chemistry, macroscopic, or microscopic abnormalities were detected 1, 2, 3, and 9 days after a single i.v. dose of ABT (50 mg/kg). A 1-hr pretreatment of beagles with ABT (20 mg/kg) decreased the clearance of intravenous phenacetin 50% and completely prevented the formation of acetaminophen. These results demonstrate that ABT pretreatment causes long-lasting inhibition of oxidative drug metabolism without disruption of normal physiological processes. Profound inhibition of oxidation in two species suggests that ABT may have general utility as an inhibitor of oxidative drug metabolism in biochemical pharmacology and toxicology studies.     

Peripheral pharmacokinetic handling and metabolism of L-dopa in the rat: the effect of route of administration and carbidopa pretreatment.

The effect of carbidopa (L-alpha-methyldopa hydrazine; 25 mg kg-1 i.p.) pretreatment on the pharmacokinetics and peripheral metabolism of orally and intra-aortically administered L-3,4-dihydroxyphenylalanine (L-dopa; 50 mg kg-1) has been examined in rats. Following intra-aortic (i.a.) administration, plasma levels of the drug declined biexponentially. Pretreatment with carbidopa resulted in higher plasma concentrations after i.a. administration of L-dopa, but had no effect on the half-life (t1/2) for its distribution or elimination. Oral L-dopa gave peak plasma concentrations at 1.5 h and then a log-linear decline between 1.5 and 6 h. Pretreatment with carbidopa also produced higher plasma concentrations of L-dopa given orally, and the t1/2 for its elimination tended to be increased compared with values achieved after the drug alone. Pretreatment with carbidopa decreased volume of distribution and total plasma clearance and increased area under the curve (0-infinity) after L-dopa i.a. and increased AUC0-infinity after L-dopa p.o. The fraction of the oral dose absorbed through the gut was not affected. Carbidopa pretreatment enhanced the accumulation of 3-O-methyldopa and decreased dopamine levels in plasma after both i.a. and oral administration of L-dopa. Higher plasma concentrations of 3,4-dihydroxyphenylacetic acid and homovanillic acid (HVA) were detected in the plasma after i.a. rather than oral administration of L-dopa and pretreatment with carbidopa greatly reduced these plasma concentrations. However, following oral L-dopa, only HVA levels were reduced by carbidopa pretreatment.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetics of the decarboxylase inhibitor benserazide in man; its tissue distribution in the rat

Summary ¹⁴C-labelled benserazide was administered to six patients with parkinsonism and total radioactivity was measured in the plasma, urine and faeces. Three patients received benserazide both orally and intravenously, while three other patients received benserazide orally alone and together with L-DOPA (= MADOPAR^®). Plasma levels did not follow first-order kinetics, but indicated rapid absorption of an oral dose. Following intravenous and oral administration, excretion of radioactivity was 88.7 and 57.7% respectively in the urine, 10.1 and 30.7% respectively in the faeces. L-DOPA slightly increased the absorption of benserazide. Following the administration of an oral dose to rats benserazide related radioactivity was distributed almost entirely outside the brain. The drug therefore appears to be suitable for blocking extracerebral decarboxylase whilst leaving the intra-cerebral enzyme almost unaffected.     

Yohimbine bioavailability in humans

Summary Pharmacokinetic profiles were determined in seven healthy young male subjects following single oral and intravenous doses of 10 mg of yohimbine hydrochloride.The drug was rapidly eliminated (t_1/2 0.58 h orally and t_1/2 0.68 h intravenously). Following intravenous administration the data fit a two-compartment pharmacokinetic model, with a very rapid distribution phase (t_1/2a was approximately 6 min). Both the oral and the intravenous yohimbine clearance values were high but oral clearance values were much higher (mean 9.77 ml·min^–1·kg^–1 intravenous versus 55.9 ml·min^–1·kg^–1 oral). The oral bioavailability showed great variability, ranging from 7% to 87% (mean value was 33%).The imcomplete oral bioavailability of yohimbine may reflect either incomplete absorption from the gastrointestinal tract or an hepatic first pass effect. Although yohimbine is rapidly absorbed when given orally, the bioavailability is quite variable and considerable individualization of dosing may be necessary when the drug is used orally for clinical indications.Supported in part by NIH grant # MOIRR 0042