Bioavailability and first-pass metabolism of oral pentazocine in man The bioavailability of oral pentazocine was studied in 5 healthy volunteers. Plasma concentrations were determined from 30 min up to 6 hr following oral administration (two 50-mg tablets) and, at other occasions, after intravenous injection of 30 mg pentazocine. The average bioavailability was found to be 18.4 ± 7.8% (SD, n = 5). It is shown that this low bioavailability depend almost entirely on the first-pass metabolism of pentazocine following oral administration by application of intravenous clearance concepts. The average beta-phase half-life was about the same following intravenous administration, 203 ± 71 (SD, n = 5) min as following oral administration, 177 ± 34 (SD, n = 5) min, with a total volume of distribution of 5.56 ± 1.63 (SD, n = 5) Llkg. It is suggested that the variations in bioavailability of orally administered pentazocine have the potential to contribute to variations in pharmacologic effects in patients.
Mats Ehrnebo, Ph.D., Lars O. Boreus, M.D., and Ulla L6nroth, B.Sc. Stockholm, Sweden Karolinska Pharmacy and Department of Clinical Pharmacology, Karolinska Hospital
A strong analgesic is often needed for clinical pain. Since such a drug is frequently selfadministered, it should have low addictive potency. Pentazocine (Talwin, Fortral) seems to fulfil these requirements relatively well. Only a few cases of abuse have been reported. An analgesic effect better than from placebo has been reported following oral doses of 50 and 70 mg pentazocine in moderate to severe pain.13 It is therefore remarkable that pharmacokinetic data on oral pentazocine are very scarce. Berkowitz and co-workers8 state that 75 mg pentazocine orally gave about the Supported by grants from the Ake Wiberg Foundation (L. O. B.) and the Swedish Medical Research Council (Project No. 522) (L. O. B.).
Received for pUblication May 3, 1977. Accepted for publication June 21, 1977. Reprint requests to: Dr. Mats Ehrnebo, Karolinska Pharmacy, Karolinska Hospital, S-I04 01 Stockholm 60, Sweden.
888
same plasma concentrations as 40 mg intramuscularly but no plasma concentration curve for oral administration was presented. The authors suggested that pentazocine may be more extensively metabolized when administered orally than by the parenteral route. Beckett, Taylor, and Kourounakis 5 suggested, on the basis of urinary excretion data, that absorption of orally administered pentazocine is either slow or incomplete, or both, and that 30% to 65% of the oral dose (given as solution) was either incompletely absorbed or cleared during absorption. Recently, Vaughan and Beckett 22 suggested that the intersubject variation in urinary output of orally administered pentazocine was due to variation in rate of metabolic oxidation. In our investigation, plasma levels of pentazocine were examined following oral and intravenous administration in the same subjects.
Oral pentazocine
Volume 22 Number 6
889
Table I. Half-lives (t1fz) and distribution volumes of pentazocine
Subjects
J. E. I. J.
S.
A.
H. K. E. E.
Range of urinary pH*
Body weight (B.W.) (kg)
t'l2 (min)
70 57 70 84 73 71 ±IO
306 121 159 234 194 203 ±71
5.4-7.2 5.5-5.9 5.5-6.5 5.7-7. I 5.5-6.4
Mean ±SD
* No premedication
l
Intravenous (Vd){3(L)
1
Oral (Vd){3IB.W. Llkg
548 251 416 503 264 396 ±136
7.83 4.40 5.94 5.99 3.62 5.56 ±1.63
tIn
(min)
204 135 145 193 207 177 ±34
to control urinary pH.
Bioavailability and other pharmacokinetic data for pentazocine were calculated which suggest a considerable first-pass effect. Material and methods
Subjects. Five healthy male subjects with body weights of 57 to 84 kg were used in the study. There was no medication, such as ammonium chloride, to control urinary pH. Three of the subjects (J. E., s.A., and H. K.) were smokers (Table I). Drug administration and sampling. Pentazocine, 30 mg (Fortalgesic, identical to Fortral, pentazocine 30 mg/ml, Winthrop Laboratories) was administered as a rapid intravenous injection. Blood samples were collected by venipuncture through an indwelling catheter prior to drug administration and at 5, 15, and 30 min and I, 2,3,4, 5, and 6 hr thereafter. Pentazocine 100 mg was also administered orally on another occasion as two 50-mg tablets (Fortalgesic, identical to Fortral, pentazocine chloride equivalent to 50 mg pentazocine, Winthrop Laboratories), together with about 100 ml of tap water. Blood samples were collected by the same method prior to and at 30 min and 1,2,3,4,5, and 6 hr after drug administration. All subjects had been fasting for 12 hr before the administration. Plasma was separated by centrifugation at room temperature and stored frozen at -18 C until time of analysis. Determination of pentazocine. Pentazocine was isolated from 2.0 ml plasma by extraction and partition chromatography as ion pair and measured fluorometrically at 282/324 nm according to the method of Borg and Mikaelsson, 9 with the following modification: The stationary 0
phase on the chromatographic column (ethanolized cellulose, Munktell 410) was O. I M HCl + 0.9 M NaCl and the mobile phase cyclohexane + I-pentanol (8.8 + 1.2). The flow rate was increased to 0.5 ml/min. Pentazocine was eluted in the 6 to II ml fraction under these conditions. The method is specific for unchanged pentazocine and has a lower limit of sensitivity of about 15 ng/m!. Calculations. The bioavailability of the oral preparation (F %) was determined by comparing the areas under the curve after oral and intravenous administration with the proper dose correction included: F%
(I)
where the areas after oral and intravenous administration, AUC oral and AUC iv , respectively, were estimated by the trapezoidal rule including the residual area up to infinite time. D iv and D oral are the doses upon intravenous and oral administration respectively. The overall elimination rate constant (f3) was estimated from the terminal portion of the plasma concentration: time curves (2 to 6 hr) using leastsquares regression analysis of the semilogarithmic plots. Half-lives (t1fz) were calculated as 0.693/f3. The total volume of distribution during the f3-phase (Vd){3 was calculated as 14 : (Vd){3 = ~. Ave fJ
(2)
IV
Total plasma clearance, Cl PL , was calculated as: CI
PL
=~= (Vd) f3 . f3 AVC iv
(3)
890
Ehrnebo, Boreus, and Lonroth
Clinical Pharmacology and Therapeutics
200
Discussion
It has been shown that the plasma concen-
E
"OJ C
Mats Ehrnebo, Ph.D., Lars O. Boreus, M.D., and Ulla L6nroth, B.Sc. Stockholm, Sweden Karolinska Pharmacy and Department of Clinical Pharmacology, Karolinska Hospital
A strong analgesic is often needed for clinical pain. Since such a drug is frequently selfadministered, it should have low addictive potency. Pentazocine (Talwin, Fortral) seems to fulfil these requirements relatively well. Only a few cases of abuse have been reported. An analgesic effect better than from placebo has been reported following oral doses of 50 and 70 mg pentazocine in moderate to severe pain.13 It is therefore remarkable that pharmacokinetic data on oral pentazocine are very scarce. Berkowitz and co-workers8 state that 75 mg pentazocine orally gave about the Supported by grants from the Ake Wiberg Foundation (L. O. B.) and the Swedish Medical Research Council (Project No. 522) (L. O. B.).
Received for pUblication May 3, 1977. Accepted for publication June 21, 1977. Reprint requests to: Dr. Mats Ehrnebo, Karolinska Pharmacy, Karolinska Hospital, S-I04 01 Stockholm 60, Sweden.
888
same plasma concentrations as 40 mg intramuscularly but no plasma concentration curve for oral administration was presented. The authors suggested that pentazocine may be more extensively metabolized when administered orally than by the parenteral route. Beckett, Taylor, and Kourounakis 5 suggested, on the basis of urinary excretion data, that absorption of orally administered pentazocine is either slow or incomplete, or both, and that 30% to 65% of the oral dose (given as solution) was either incompletely absorbed or cleared during absorption. Recently, Vaughan and Beckett 22 suggested that the intersubject variation in urinary output of orally administered pentazocine was due to variation in rate of metabolic oxidation. In our investigation, plasma levels of pentazocine were examined following oral and intravenous administration in the same subjects.
Oral pentazocine
Volume 22 Number 6
889
Table I. Half-lives (t1fz) and distribution volumes of pentazocine
Subjects
J. E. I. J.
S.
A.
H. K. E. E.
Range of urinary pH*
Body weight (B.W.) (kg)
t'l2 (min)
70 57 70 84 73 71 ±IO
306 121 159 234 194 203 ±71
5.4-7.2 5.5-5.9 5.5-6.5 5.7-7. I 5.5-6.4
Mean ±SD
* No premedication
l
Intravenous (Vd){3(L)
1
Oral (Vd){3IB.W. Llkg
548 251 416 503 264 396 ±136
7.83 4.40 5.94 5.99 3.62 5.56 ±1.63
tIn
(min)
204 135 145 193 207 177 ±34
to control urinary pH.
Bioavailability and other pharmacokinetic data for pentazocine were calculated which suggest a considerable first-pass effect. Material and methods
Subjects. Five healthy male subjects with body weights of 57 to 84 kg were used in the study. There was no medication, such as ammonium chloride, to control urinary pH. Three of the subjects (J. E., s.A., and H. K.) were smokers (Table I). Drug administration and sampling. Pentazocine, 30 mg (Fortalgesic, identical to Fortral, pentazocine 30 mg/ml, Winthrop Laboratories) was administered as a rapid intravenous injection. Blood samples were collected by venipuncture through an indwelling catheter prior to drug administration and at 5, 15, and 30 min and I, 2,3,4, 5, and 6 hr thereafter. Pentazocine 100 mg was also administered orally on another occasion as two 50-mg tablets (Fortalgesic, identical to Fortral, pentazocine chloride equivalent to 50 mg pentazocine, Winthrop Laboratories), together with about 100 ml of tap water. Blood samples were collected by the same method prior to and at 30 min and 1,2,3,4,5, and 6 hr after drug administration. All subjects had been fasting for 12 hr before the administration. Plasma was separated by centrifugation at room temperature and stored frozen at -18 C until time of analysis. Determination of pentazocine. Pentazocine was isolated from 2.0 ml plasma by extraction and partition chromatography as ion pair and measured fluorometrically at 282/324 nm according to the method of Borg and Mikaelsson, 9 with the following modification: The stationary 0
phase on the chromatographic column (ethanolized cellulose, Munktell 410) was O. I M HCl + 0.9 M NaCl and the mobile phase cyclohexane + I-pentanol (8.8 + 1.2). The flow rate was increased to 0.5 ml/min. Pentazocine was eluted in the 6 to II ml fraction under these conditions. The method is specific for unchanged pentazocine and has a lower limit of sensitivity of about 15 ng/m!. Calculations. The bioavailability of the oral preparation (F %) was determined by comparing the areas under the curve after oral and intravenous administration with the proper dose correction included: F%
(I)
where the areas after oral and intravenous administration, AUC oral and AUC iv , respectively, were estimated by the trapezoidal rule including the residual area up to infinite time. D iv and D oral are the doses upon intravenous and oral administration respectively. The overall elimination rate constant (f3) was estimated from the terminal portion of the plasma concentration: time curves (2 to 6 hr) using leastsquares regression analysis of the semilogarithmic plots. Half-lives (t1fz) were calculated as 0.693/f3. The total volume of distribution during the f3-phase (Vd){3 was calculated as 14 : (Vd){3 = ~. Ave fJ
(2)
IV
Total plasma clearance, Cl PL , was calculated as: CI
PL
=~= (Vd) f3 . f3 AVC iv
(3)
890
Ehrnebo, Boreus, and Lonroth
Clinical Pharmacology and Therapeutics
200
Discussion
It has been shown that the plasma concen-
E
"OJ C
