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The following message was posted to: PharmPK
Dear all,
I have read the article 'Influencing of aging on serum phenytoin
concentration:...' published in Epilepsy Reseach 59 (2004) 155-165.
The author calculated Cl/F from measured serum phenytoin levels
gathered from retrospective data.
They compare Cl/F between two patient groups: control (age 20-50) and
elderly (65-90 years old).
The mean Cl/F in elderly group was 14.6 mL/hr/kg vs. 13.1 mL/hr/kg in
Control group (P <0.05).
This seem clearance in elderly group were significantly higher than
in control group.
However, they explained that elderly patients received lower dosages
[4.4 mg/kg/day vs. 5.3 mg/kg/day] and had lower total phenytoin level
(14.1 vs. 18.6 mg/L). Also the free fraction is also known to
increase with age.
Do you think if this message can imply that the metabolism of
phenytoin is decreased in elderly patients?
The author further illustrated that Cl/F decreased by one-third
between 65 and 85 years of age, but interindividual variability was
considerable and age explained only 7.8% of the variation in Cl/F in
the elderly group.
They finally concluded that aging is associated with a progressive
decline in phenytoin clearance, presumably as a result of decreased
drug metabolizing capacity, and suggested the intial smaller dosage
in this patient group.
Do you agree with this conclusion?
I think that the increased free fraction of phenytoin in the elderly
may account mainly for the lower initial dosage recommendation and
the reduction in phenytoin clearance is still questionable based on
this study (there are many confounding variables: bioavailability,
dose, free fraction, interindividual variablility, and sensitivity of
clearance to change in the dose and drug level).
Also, is comparison of Cl/F appropriate enough for this purpose (with
this nonlinear drug)? They said that calculation for Vmax and Km is
unreliable, and that's why they chose to calculate Cl/F.
The second question: In 1st order elimination process, is fractional
renal clearance stable in the elimination phase?
I'm not so familiar with the term 'fractional clearance', could
anyone explain it more?
And the final question: If terminal half-life calculated from Cp
data and Urinary data (rate method and amount of drug remaining to be
excreted method) are different, what is the major cause of this
difference? The terminal half-lives calculated from urinary data
(both methods from slope) were similar, but significantly different
from that calculated from Cp. I think of the degradation of the drug
in urine samples. Is this the major source of the observed
differences you found in your most experiments.
Any kind of comments are very appreciated.
Dr. Sarawut Oo-puthinan
Sarawut OO-PUTHINAN, Ph.D.
Faculty of Pharmaceutical Sciences,
Naresuan University, Thailand
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The following message was posted to: PharmPK
Dear Sarawut,
I did not read the article 'Influencing of aging on serum
phenytoin concentration:...' published in Epilepsy
Reseach 59 (2004) 155-165, but I will try to make some
comments on your notes.
> The author calculated Cl/F from measured serum phenytoin
>levels gathered from retrospective data.
> They compare Cl/F between two patient groups: control
>(age 20-50) and elderly (65-90 years old).
> The mean Cl/F in elderly group was 14.6 mL/hr/kg vs.
>13.1 mL/hr/kg in Control group (P <0.05).
> This seem clearance in elderly group were significantly
>higher than in control group.
> However, they explained that elderly patients received
>lower dosages [4.4 mg/kg/day vs. 5.3 mg/kg/day] and had
>lower total phenytoin level (14.1 vs. 18.6 mg/L). Also
>the free fraction is also known to increase with age.
> Do you think if this message can imply that the
>metabolism of phenytoin is decreased in elderly
>patients?
The situation is quite complex, since phenytoin is known
to be eliminated in a nonlinear way. Therefore CL is not
constant, and conclusions cannot be drawn. From the data
in your message one can conclude that the apparent CL/F in
elderly patients is slightly higher (4.4 / 14.1 = 0.312
l/kg/day) in elderly compared to control (5.3 / 18.6 0.285 l/kg/day).
In addition, changed plasma protein binding complicates
the matter. If fu is higher in elderly patients, the
reported values for total phenytoin may be associated with
comparable unbound concentrations. However, if the change
in fu is larger than about 10%, the unbound concentrations
in the elderly may be even higher than in controls, and a
further dose reduction may be required.
Please note that a change in plasma protein binding is not
a reason for dose adjustment, since fu does not affect the
unbound concentration in steady state. However, the
increase in fu may mask the decrease of metabolic capacity
as expressed in intrinsic clearance, or Vmax in case of
nonlinear kinetics. So, the apparently increased value of
CL/F is not likely to be the result of an increased
metabolic capacity, but the net result of a decrease in
intrinsic clearance (Vmax/Km) and an increase of fu. Both
effect may be related to age, but are not correlated in a
mechanistic sense.
> They finally concluded that aging is associated with a
>progressive decline in phenytoin clearance, presumably
>as a result of decreased drug metabolizing capacity, and
>suggested the intial smaller dosage in this patient
>group.
> Do you agree with this conclusion?
I think this conclusion is correct, but this cannot be
concluded from the data in your message alone.
> I think that the increased free fraction of phenytoin in
>the elderly may account mainly for the lower initial
>dosage recommendation and the reduction in phenytoin
>clearance is still questionable based on this study
>(there are many confounding variables: bioavailability,
> dose, free fraction, interindividual variablility, and
>sensitivity of clearance to change in the dose and drug
>level).
I don't agree. As stated above, an increase of fu is not a
reason for a lower (initial) dosage recommendation in
elderly patients. The only clinically relevant reason for
adjusting the dose is a decrease in intrinsic clearance.
Bioavailability of phenytoin is not likely to be a major
issue, since it is rather high, and important variability
will be largely in the direction of a lower
bioavailability.
> Also, is comparison of Cl/F appropriate enough for this
>purpose (with this nonlinear drug)? They said that
>calculation for Vmax and Km is unreliable, and that's
>why they chose to calculate Cl/F.
It is questionable whether or not the comparison of CL/F
is appropriate for phenytoin due to its nonlinear
characteristics. With respect to protein binding, CL/F is
not a good parameter for comparison, as stated above.
> The second question: In 1st order elimination process,
>is fractional renal clearance stable in the elimination
>phase?
Renal elimination is only a minor route of elimination for
phenytoin, so I don't think this relevant. Anyhow, renal
clearance and metabolic clearance are independent
(although both affected by plasma protein binding).
> I'm not so familiar with the term 'fractional
>clearance', could anyone explain it more?
This is a strange expression. I think you mean fe, the
fraction excreted unchanged, which equals
CL_renal/CL_total.
> And the final question: If terminal half-life
>calculated from Cp data and Urinary data (rate method
>and amount of drug remaining to be excreted method) are
>different, what is the major cause of this difference?
> The terminal half-lives calculated from urinary data
> (both methods from slope) were similar, but
>significantly different from that calculated from Cp. I
>think of the degradation of the drug in urine samples.
> Is this the major source of the observed differences
>you found in your most experiments.
Half-life in plasma and urine should be the same. However,
in case of nonlinear kinetics, half-life is not constant.
So, if half-life in plasma and urine are determined over
different time periods, i.e. where the plasma
concentration is different, the value obtained for
half-life with be different. Degradation of phenytoin in
urine samples seems rather unlikely, but I have no
knowledge about this.
Best regards,
Hans Proost
Johannes H. Proost
Dept. of Pharmacokinetics and Drug Delivery
University Centre for Pharmacy
Antonius Deusinglaan 1
9713 AV Groningen, The Netherlands
tel. 31-50 363 3292
fax 31-50 363 3247
Email: j.h.proost.at.rug.nl
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